TWI238155B

TWI238155B - Methods for preparing aryl ethers, the intermediates therefor and methods for preparing the intermediates

Info

Publication number: TWI238155B
Application number: TW088122940A
Authority: TW
Inventors: Kevin E Henegar; Sarah Elizabeth Mancini; Keith Douglas Maisto
Original assignee: Upjohn Co
Priority date: 1998-12-29
Filing date: 1999-12-24
Publication date: 2005-08-21
Also published as: IL144012A; ATE260238T1; HK1041688B; PT1140788E; KR20010099999A; IL161840A0; EP1308443A3; SI1140788T1; EP1308443B1; AU2381900A; PE20001366A1; JP2002533430A; CN1332719A; ATE430144T1; ES2214060T3; HUP0202144A2; CN1308332C; CA2349619A1; US6376711B1; AU764492B2

Abstract

The invention relates to a method for preparing aryl ethers that are useful as antidepressants. The invention also relates to intermediates useful in the method and to methods for preparing such intermediates.

Description

12381551238155

五、發明說明（3 其中R爲Ci_C；6燒氧基或二齒甲| 、 111 虱基次一 _甲基。所揭示之這些非鏡像V. Description of the invention (3 in which R is Ci_C; 6-alkoxy or bidentate || 111 phenylene_methyl. These disclosed non-mirrored

異構物係製備彳P4 Λ 4 A A p k 備化學式A l化合物的中間體，包括 :—是有用的。然而，在這些專利和美國專利第 ::9,449唬中揭示之方法無效，且提供化學式a之化合物你王面低產率，當以商業規模進 <于時。此外，該方法需要吏用昂貴試劑且需要相當之生產時間。因此，使用這些專利中所揭示之方法以商業規模製備化學式A之化合物是不經濟的。與因此，近來需要製備化學式（A)之化合物和用以製備化學式(A)之化合物之中間體的改良方法。理想上，該改良方法應該使用不昂貴之試劑，進行較迅速，或提供相較於現存之方法之改良中間體或整體產率。此改良處促進化學式（A)之化合物的商業規模生產。發明搞要：如圖π中所説明般，本發明提供一種化學式VIIa之胺的製備方法： ⑻ΓIsomers are useful for the preparation of 彳 P4 Λ 4 A A p k intermediates for compounds of formula A1, including:-. However, the methods disclosed in these patents and U.S. Patent No. :: 9,449 are ineffective and provide compounds of formula A. Your yield is low when it is commercially available. In addition, this method requires expensive reagents and requires considerable production time. Therefore, it is not economical to prepare the compound of formula A on a commercial scale using the methods disclosed in these patents. Therefore, recently, there is a need for an improved method for preparing a compound of the formula (A) and an intermediate for preparing the compound of the formula (A). Ideally, the improved method should use less expensive reagents, run more quickly, or provide improved intermediates or overall yields compared to existing methods. This improvement facilitates the commercial-scale production of compounds of formula (A). Summary of the Invention: As illustrated in FIG. Π, the present invention provides a method for preparing an amine of formula VIIa: ⑻Γ

經濟部智慧財產局員工消費合作社印製 ΡΓΟ NH2Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs ΡΓΟ NH2

Vila 其包括： a) 將視需要取代之反式4圭皮醇氧化，得到化學式i a之 -6- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公爱） 1238155Vila includes: a) Oxidation of trans 4 guapitol as needed to obtain the chemical formula i a-6-This paper size applies Chinese National Standard (CNS) A4 (210 X 297 public love) 1238155

五、發明說明（4 ) 中間體環氧化物〇 ⑻)niV. Description of the invention (4) Intermediate epoxide 〇 ⑻) ni

OH la b)將孩環氧化物與視需要取代之苯驗反應，得到化學式Ila之二醇：一OH la b) reacting epoxide with optionally substituted benzene to obtain a diol of formula Ila: a

c) 醇：將該二醇與矽烷化試劑反應，得到化學式nia 之 I · ί --------^------ (請先閱讀背面之注意事項再填寫本頁)c) Alcohol: The diol is reacted with a silylation reagent to obtain I · ί of the chemical formula nia -------- ^ ------ (Please read the precautions on the back before filling this page)

(Ri)ni 經濟部智慧財產局員工消費合作社印製其中P爲一種矽烷基鍵聯反應基； d) 將化學式Ilia之醇與磺酸之反應性衍生物反應到化學式IVa之化合物：本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公爱）得 1238155 A7 B7 五、發明說明（5 )(Ri) ni Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, where P is a silane-based reactive group; d) Reacting a reactive derivative of an alcohol of the chemical formula Ilia with a sulfonic acid to a compound of the chemical formula IVa: Applicable to China National Standard (CNS) A4 specification (210 X 297 public love) 1238155 A7 B7 V. Invention description (5)

其中R a爲磺酸之殘基； e) 將P從化學式IVa之化合物移除，得到化學式Vat 醇.-: - /Where R a is a residue of sulfonic acid; e) removing P from the compound of formula IVa to obtain the alcohol of formula Vat.-:-/

f) 將磺醯氧基取代，得到化學式Via之環氧化物： 0 I n n ϋ n n n 1 n n «ϋ 0 n 8fl (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製f) Substitute the sulfonyloxy group to obtain the epoxide of the formula Via: 0 I nn ϋ nnn 1 nn «ϋ 0 n 8fl (Please read the notes on the back before filling out this page) Employee Cooperative of Intellectual Property Bureau, Ministry of Economic Affairs Print

g) 將該環氧化物與氨反應，得到化學式Vila之化合物0 如圖III所説明般，本發明亦提供一種方法，其更包括： -8- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐）訂---------· 1238155 A7 B7 五、發明說明（6 ) h) 將化學式Vila之化合物g) The epoxide is reacted with ammonia to obtain compound 0 of the chemical formula Vila. As illustrated in FIG. III, the present invention also provides a method, which further includes: -8- This paper size is applicable to Chinese National Standard (CNS) A4 (210 X 297 mm) Order --------- · 1238155 A7 B7 V. Description of the invention (6) h) The compound of the formula Vila

(Ri)m Vila 與化學式HO〇eCH2L·之羧酸或其反應性衍生物反應，其中 L爲離去基，得到化學式Villa之醯胺··(Ri) m Vila is reacted with a carboxylic acid of the chemical formula HO〇eCH2L · or a reactive derivative thereof, where L is a leaving group to obtain amidamine of the chemical formula Villa ··

i) 將化學式Villa之化合物反應合物反應： · 得到化學式IXa之化 (請先閱讀背面之注意事項再痕寫本頁) .黍訂--- 筹· 經濟部智慧財產局員工消費合作社印製且 (^)n IXai) React the compound reaction compound of the chemical formula Villa: · Get the chemical formula of IXa (please read the precautions on the back before writing this page). Customized --- printed by the Intellectual Property Bureau of the Ministry of Economic Affairs, printed by the Consumer Cooperative And (^) n IXa

-9- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 1238155 A7 B7 五、發明說明（7 ) j) 將化學式IXa之化合物還原，得到應化合物：以下化學式之對 (R)n-9- This paper size is in accordance with Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1238155 A7 B7 V. Description of the invention (7) j) The compound of chemical formula IXa is reduced to obtain the corresponding compound: R) n

經濟部智慧財產局員工消費合作社印製本發明亦提供此處所揭示之新穎中間體（例如化學式 V和IIIa-Va之化合物），以及其合成方法。發明詳述：使用以下定義，除非特別敘述：肩基爲氟基，氣基，溪基或破基。燒基，燒氧基，烯基，炔基等等，表示直缝和支鏈基；但參照爲如”丙基”之獨立反應基僅包括直鏈反應基’尤其參照如”異丙基"之支健異構物。芳基表示苯基或具有約9至1 0個環原子之鄰位稠環二環碳環系反應基’其中r至·少一個環爲芳香族。"商業規模"表示足以分_ 配予大量消費者之許多-公斤量，例如至少約1 〇公斤，約 100公斤，或約1000公斤材料。諳熟此藝者將預期化學式（A)之化合物和此處敘述之中間體具有一對掌中心，其以光學活性且消旋形式存在並被分離。一些化合物可以呈現同質多晶形性。咸瞭解本發明包括任何外消旋，光學活性，同質多晶形性，或立體異構物形式，或其混合物，於該技藝中咸知如何製備光學活性形式（例如以再結晶技術將.外消旋形式解析，以從光學活 -10- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） — rilli (請先閱讀背面之注意事項再填寫本頁) 訂-----------線秦 1238155Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economics The present invention also provides novel intermediates (such as compounds of Chemical Formulas V and IIIa-Va) disclosed herein, as well as methods for their synthesis. DETAILED DESCRIPTION OF THE INVENTION: The following definitions are used unless specifically stated: the shoulder group is a fluorine group, a gas group, a stream group or a broken group. Alkenyl, alkoxy, alkenyl, alkynyl, etc., represent straight and branched chains; however, independent reactive groups referred to as "propyl" include only straight-chain reactive groups, and especially referenced as "isopropyl" Is a branched isomer. Aryl means phenyl or ortho-fused ring bicyclic carbocyclic ring system reactive group having about 9 to 10 ring atoms, wherein at least one ring is aromatic. &Quot; Commercial Scale " indicates a quantity of many-kilograms sufficient to distribute to a large number of consumers, such as at least about 10 kilograms, about 100 kilograms, or about 1,000 kilograms of material. Those skilled in the art will expect compounds of formula (A) and here The described intermediate has a pair of palm centers that exist and are isolated in optically active and racemic forms. Some compounds can exhibit homomorphic polymorphisms. It is understood that the invention includes any racemic, optically active, homogeneous polymorphisms, Or stereoisomeric forms, or mixtures thereof, know how to prepare optically active forms in this technology (for example, resolving racemic forms with recrystallization technology to convert optically active forms from -10- (CNS) A4 Specifications 210 X 297 mm) - rilli (Read the back of the precautions to fill out this page) book ----------- line Qin 1,238,155

經濟部智慧財產局員工消費合作社印製 :ΪΓ。材料合成，以對掌合成，或以使用對掌靜止相層析本發明之方法能夠製備化學式Α之化合物的單一非混合物’和此處揭示之中間體。咸瞭解能夠使:該云中已知之技術將此類混合物分離爲對應鏡像異構物。因此’本"亦提供製備化學式（A)之單—鏡像異構物，以及任何此處所揭示中間體化合物之單—鏡像異構物。較佳之化合物具有對應Reboxetine立體化學之立體化學。以下關於反應基，取代基所列之特定且較佳數値5和範圍僅用以說明；其不排除其它已定義之數値或其它在關於反應基和取代基所定義内之數値。尤其’ η爲1。尤其’ η 1爲1。尤其’R爲氫，鹵基，三氟甲烷，羥基，（^-(^烷氧基， CVG燒基，芳基_Cl-C6烷基，芳基-CVC6烷氧基，硝基，或 NR5R6 〇尤其，η爲2，且二個鄰近R基形成亞甲二氧基。尤其’R!爲氫，氣基，三氟甲垸，輕基，Ci-Cs燒氧基’ CVC6虎基，芳基-Ci-C6燒基，芳基-Ci-C6規氧基，硝基，或 NR5R6。尤其，irl爲2，且二個鄰近Ri基形成亞曱二氧基。尤其，R5和116各爲氫。尤其’ R〗爲鼠’甲基，乙基，苯基，爷基或苯乙基。尤其，R3和R4各爲氫。 -11- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） !!——#--------tT---------華 (請先閱讀背面之注意事項再填寫本頁) 1238155 A7Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs: ΪΓ. Material synthesis, either with palmar or stationary phase chromatography using palmar The method of the present invention enables the preparation of a single non-mixture of compounds of formula A 'and intermediates disclosed herein. This understanding enables technology known in the cloud to separate such mixtures into corresponding mirror isomers. Accordingly, the present " provides also the preparation of the mono-mirro isomers of formula (A), as well as the mono-mirro isomers of any of the intermediate compounds disclosed herein. A better compound has a stereochemistry corresponding to the Reboxetine stereochemistry. The specific and preferred numbers 5 and ranges listed below with respect to reactive groups and substituents are for illustration only; they do not exclude other defined numbers or other numbers within the definitions of reactive groups and substituents. In particular, 'η is 1. In particular, 'η 1 is 1. In particular, 'R is hydrogen, halo, trifluoromethane, hydroxyl, (^-(^ alkoxy, CVG alkyl, aryl-Cl-C6 alkyl, aryl-CVC6 alkoxy, nitro, or NR5R6 〇 In particular, η is 2, and two adjacent R groups form a methylenedioxy group. In particular, 'R! Is hydrogen, a gas group, a trifluoromethane group, a light group, a Ci-Cs alkoxy group, a CVC6 tiger group, and an aromatic group. -Ci-C6 alkyl, aryl-Ci-C6 ethoxy, nitro, or NR5R6. In particular, irl is 2 and two adjacent Ri groups form a fluorenyldioxy group. In particular, R5 and 116 are each Hydrogen. In particular, 'R' is rat 'methyl, ethyl, phenyl, hexyl, or phenethyl. In particular, R3 and R4 are each hydrogen. -11- This paper size applies to China National Standard (CNS) A4 specifications ( 210 X 297 mm) !! —— # -------- tT --------- Hua (Please read the notes on the back before filling this page) 1238155 A7

五、發明說明（9 ) 、其，R3和I中至少一個爲視需要取代之烷基， c：2^4烯基，eye#炔基，視需要取代之芳基烷基，視而要取代< C^C7環烷基，或R3和R4與其鍵結之氮原子 :起成爲嗎啉基，六氫吡啶基，N-比咯啶基，N_甲基_六氫吡畊基或N -苯基-六氫吡畊基。尤其R2和I-起形成_CH2_CH2_反應基；且1爲氫。尤其，無論何時一個基能夠被“一個或多個，，反應基取代，該基能夠被至少i，2或3反應基取代。一個化合物之較佳族群爲其中11爲1且尺爲2_甲氧基或1 乙氧基之化合物。另一個化合物之較佳族群爲其中111爲1且心爲氫或自基之化合物。美國專利第4,229,449，5,068,433和5,391，735號提供其中所述取代基和基之某些特定且較佳之數値。咸瞭解這些特定且較佳數値對於此處所述對應取代基和基亦爲特定且較佳之數値。例如’美國專利第4,229,449號包括關於其中之取代基和基之以下敘述： a) 燒基，烯基，块基和烷氧基可以是直鏈或支鏈； b) 當化和反1基中一個或多個爲取RCrC6烷基時，較佳 Ci-C6；fe基係被一個或多個擇自邊基，Cl_c6燒氧基，-NR5R6或-C(=0)NR5R6之取代基取代； c) 芳基較佳爲苯基； d) 當仏和R4基中一個或多個爲取代CrC6烷基時，較佳Crc0烷基係被一個或多個擇自鹵素，羥基，Ci_ -12- 用中國國家標準（CNS)A4規格（210 X 297公釐） (請先閱讀背面之注意事項再填寫本頁)V. Description of the invention (9), wherein at least one of R3 and I is an alkyl group substituted as needed, c: 2 ^ 4 alkenyl, eye # alkynyl, substituted arylalkyl if necessary, and substituted if necessary < C ^ C7 cycloalkyl, or nitrogen atom to which R3 and R4 are bonded: from morpholinyl, hexahydropyridyl, N-pyrrolidyl, N_methyl_hexahydropyridyl or N -Phenyl-hexahydropyridyl. In particular, R2 and I- form a _CH2_CH2_ reactive group; and 1 is hydrogen. In particular, whenever a group can be substituted with "one or more, reactive groups, that group can be substituted with at least i, 2 or 3 reactive groups. A preferred group of compounds is 11 where 1 is 1 and the ruler is 2_A. Oxy or 1 ethoxy compounds. Another preferred group of compounds are those in which 111 is 1 and the heart is hydrogen or self-radical. U.S. Patent Nos. 4,229,449, 5,068,433 and 5,391,735 provide the substituents and Certain specific and preferred numbers of radicals. It is understood that these specific and preferred numbers are also specific and preferred for the corresponding substituents and radicals described herein. For example, U.S. Patent No. 4,229,449 includes information on these. The following descriptions of the substituents and groups: a) alkyl, alkenyl, bulk and alkoxy may be straight or branched; b) when one or more of the alkyl and trans 1 groups are RCrC6 alkyl, Preferred Ci-C6; the fe group is substituted with one or more substituents selected from the side group, Cl_c6 alkoxy, -NR5R6 or -C (= 0) NR5R6; c) the aryl group is preferably phenyl; d ) When one or more of the fluorene and R4 groups are substituted CrC6 alkyl groups, it is preferred that the Crc0 alkyl group be substituted by one Choose from more halogen, hydroxy, Ci_ -12- with China National Standard (CNS) A4 size (210 X 297 mm) (Please read the back of the precautions to fill out this page)

- ϋ n I ·1 n ϋ n « ^ 6 ai_— n I 經濟部智慧財產局員工消費合作社印製 1238155 A7 B7 經濟部智慧財產局員工消費合作社印製五、發明說明（1〇 ) c6烷氧基，-NR5R6或-C(=〇)NR5R6之取代基取代；該相同取代基可以存在於取代C1_C12烷基上； e) 取代芳基-Ci-C6燒基，芳基-CVC4燒基和芳基烷氧基較佳爲芳基烷基，芳基烷基和芳基- Ci-C(5燒氧基’其中該芳基係被一個或多個Ci_ C6：fe基，鹵素，鹵基-Ci-C6燒基，巍基，Ci-Cs燒氧基和-NR5R6取代； f) 取代C3_C；7環抗基係被一個或多個較佳擇自（^(^燒基，卣素，卣基-Ci-C6烷基，羥基，（^(^烷氧基和 -NR5R6t取代基取代的c3-C7取代基； g) Ci_C6抗基較佳爲甲基’乙基或異丙基； h) ci-C!2院基較佳爲甲基，乙基，異丙基或辛基； i) C^C：4烯基較佳爲乙烯基或烯丙基；C2_c4炔基較佳爲块丙基； j) 鹵基-Ci-C6烷基較佳爲三鹵基_Cl_C6烷基，尤指三氟甲基； k) 氧基較爲甲氧基或乙氧基； l) 方基-Ci_C6fei基或方基-C1-C4抗基較佳爲爷基或苯乙基； m) 芳基<!-(：6烷氧基較佳爲苄氧基； η) 在-NE^R6基中，R5和R0較佳獨立爲氫或c〗_c3燒基. 尤指甲基，乙基或異丙基；〇 ) C3_C7環：fe基較佳爲環丙基，環戊基或環己基· P)當I和R4,與其键連之氮原子一起形成一種取代雜 (請先閱讀背面之注意事項再填寫本頁) t -13--ϋ n I · 1 n ϋ n «^ 6 ai_— n I Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 1238155 A7 B7 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 5. Description of the invention (1〇) c6 Alkoxy Group, -NR5R6 or -C (= 〇) NR5R6 substituent; the same substituent may be present on the substituted C1-C12 alkyl; e) substituted aryl-Ci-C6 alkyl, aryl-CVC4 alkyl and aryl The alkoxy group is preferably an arylalkyl group, an arylalkyl group, and an aryl-Ci-C (5 alkyl group 'wherein the aryl group is substituted by one or more Ci_C6: fe group, halogen, halo- Ci-C6 alkyl, Wei, Ci-Cs alkyl and -NR5R6 are substituted; f) C3_C is substituted; the 7-ring antibody is selected from one or more of the following: -Ci-C6 alkyl, hydroxy, (^ (^ alkoxy and -NR5R6t substituted c3-C7 substituents; g) Ci_C6 antibody is preferably methyl 'ethyl or isopropyl; h) Ci-C! 2 is preferably methyl, ethyl, isopropyl or octyl; i) C ^ C: 4 alkenyl is preferably vinyl or allyl; C2_c4 alkynyl is preferably propylene J) halo-Ci-C6 alkyl is preferably trihalo_Cl_C6 alkyl, especially tri Methyl group; k) oxy group is more methoxy or ethoxy group; l) square group-Ci_C6fei group or square group-C1-C4 resist group is preferably hexyl group or phenethyl group; m) aryl group <! -(: 6 alkoxy group is preferably benzyloxy group; η) In the -NE ^ R6 group, R5 and R0 are preferably independently hydrogen or c ??-c3 alkyl group. Especially methyl, ethyl or isopropyl 〇) C3_C7 ring: Fe group is preferably cyclopropyl, cyclopentyl or cyclohexyl. P) When I and R4, it forms a kind of substituted hetero with its bonded nitrogen atom (please read the notes on the back before filling in (This page) t -13-

1238155 A7 B7 q) 如如丁成產經濟部智慧財產局員工消費合作社印製五、發明說明（11 單環反應基時，該取代基較佳爲Cl-C6烷基或芳基，尤指甲基或苯基；較佳之雜單環反應基爲嗎琳基，六氫吡啶基，N -比咯啶基，n -甲基-六氫吨唯基和N -苯基-六氫吡畊基；和當二個鄰近R基或二個鄰近&基形成小-CH2_〇-反應基時，此較佳爲3,4-亞甲二氧基。美國專利第4,229,449號亦揭示化學式（A)之化合物能夠被調配爲製藥可接受之鹽類，包括具無機酸之鹽類，例氮氯酸，氫溴酸，和硫酸；且包括具有機酸之鹽類，例檸檬酸，酒石酸，甲烷磺酸，反丁烯二酸，蘋果酸，順烯二酸和苯乙醇酸。揭示較佳之鹽類爲與胺基项心心形之酸鹽類（例如氫氯酸或甲烷磺酸鹽）。因此，本發明中生化學式（A)之化合物的方法亦可以視需要地更包括製化學式（A)之化合物之鹽類。製藥可接受之鹽類可以使該技藝中已知之標準步驟得到。將以下化學式之視需要取代反式桂皮醇： (^{)nl1238155 A7 B7 q) For example, printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs of Dingcheng, printed by the fifth, the invention description (11 in the case of a monocyclic reactive group, the substituent is preferably Cl-C6 alkyl or aryl, especially nail Phenyl or phenyl; preferred heteromonocyclic reactive groups are morphinyl, hexahydropyridyl, N-pyrrolidyl, n-methyl-hexahydrotyl and N-phenyl-hexahydropyridyl And when two adjacent R groups or two adjacent & groups form a small -CH2_0-reactive group, this is preferably 3,4-methylenedioxy. US Patent No. 4,229,449 also discloses the chemical formula (A ) Compounds can be formulated into pharmaceutically acceptable salts, including salts with inorganic acids, such as chloric acid, hydrobromic acid, and sulfuric acid; and include salts with organic acids, such as citric acid, tartaric acid, methane Sulfonic acid, fumaric acid, malic acid, maleic acid, and phenylglycolic acid. Preferred salts are disclosed as heart-shaped acid salts (such as hydrochloric acid or methanesulfonate) with an amine base. Therefore The method of the compound of the chemical formula (A) in the present invention may further include, as necessary, salts of the compound of the chemical formula (A) Pharmaceutically acceptable salts thereof can be made of standard procedures known in the art obtained by the following Chemical Formulas optionally substituted trans-cinnamic alcohol:. (^ {) Nl

得到化學式la之環氧化物之環氧化能夠便利地使用適冬環氧化劑進行，例如㈣奸和過氧化氫，M(乙酿丙嗣)'和二級丁基化過氧氫，或如過氧苯甲酸，m•氯過氧苯甲酸，過氧乙酸，過氧三氟乙酸或單_或二過氧自太酸之過氧故。反應能夠在任何適當溶劑或溶劑組合物中進行，例如 -14- 本紙張尺度顧巾關家鮮（CNS)A4規格 (請先閱讀背面之注意事項再填寫本頁}The epoxidation of the epoxides with the chemical formula la can be conveniently carried out using winter-appropriate epoxidants, such as rape and hydrogen peroxide, M (ethyl alcohol), and secondary butylated hydrogen peroxide, or as peroxygen. Benzoic acid, m • chloroperoxybenzoic acid, peroxyacetic acid, peroxytrifluoroacetic acid, or mono- or diperoxy from peroxyacid. The reaction can be carried out in any suitable solvent or solvent composition, such as -14- This paper is scaled with GuSuanguan (CNS) A4 specifications (Please read the precautions on the back before filling this page}

Ϊ238155Ϊ238155

五、發明說明〇!2 2 ’自化烴，直鏈或支鏈醚，羧酸或酯。特定實例包栝 ’甲苯’氣仿，二氯甲烷，二***，二嘮烷，乙酸和乙 '酉曰較佳反應係在二氣甲燒或乙酸乙g旨中進行。在二氧甲中更佳。反應能夠在從反應混合物冰點至迴流點之任何適當溫度進行。較佳反應係在約至約5〇t之溫度圍内進行。更佳係在約5°c至約25°c之溫度範圍内進行。美國專利第5,068,433號和相關之美國專利第5,391，735號揭示，化學式lb之環氧化物能夠從反式桂皮醇使用適當氧化劑製備，例如釩酸酐和過氧化氫，或過氧酸，例如過氧苯甲酸，m -氯過氧苯曱酸，過氧乙酸，單-或二-過氧酞酸，或過氧-三氟乙酸。在實例1，這些專利尤其例證經由以m -氯過氧苯甲酸將反式桂皮醇氧化而製備化學式 lb之環氧化物。以m•氯過氧苯甲酸將反式桂皮醇氧化亦由 P·梅洛林（Melloni) et al·四面體（Tetrahedron )，1 9 8 5， 4 1，編號7，1393_1399 提出。 m-氯過氧苯甲酸用於商業規模是昴貴的。因此，各種環氧化試劑對於以商業規模（A)之化合物將是較佳。以單 -過氧-酞酸之研究頃顯示此試劑能夠被用以在商業規模製備環氧化物lb。然而，從酞酸酐和過氧化氫製備單_過氧— 酞酸是耗時的。此外，與單·過氧-酞酸之環氧化反應產生大量固體酞酸副產物，其必需從產物混合物過濾。此過濟、步驟耗時並產生大量水性和固體廢物。因此，m_氯過氧苯甲酸和單-過氧-酞酸理想上並不適於反式桂皮醇之商業 -15- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） "----- --------訂—------ (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 1238155 A7 -- —____B7__五、發明說明（13 ) 規模環氧化反應。頃發現桂皮醇之環氧化能夠便利地使用過氧乙酸以商業規模進行。過氧乙酸較不筇貴，且爲液體，係比固體之氯過氧苯曱酸更易於大規模處理。此外，使用過氧乙酸藉由刪除製備單-過氧-酞酸之需求降低製備環氧化物几所需之時間；相較於與單_過氧-酞酸之反應，過氧乙酸亦相當地降低由環氧化反應產生之水性和固體廢物量。因此，本發明提供一種化學式Ia之環氧化物製備方法：V. Description of the Invention 〇 2 2 'Self-hydrocarbons, linear or branched ethers, carboxylic acids or esters. Specific examples include 'toluene' aerosol, dichloromethane, diethyl ether, dioxane, acetic acid and ethyl. The preferred reaction is carried out in dioxane or ethyl acetate. Better in Dioxane. The reaction can be carried out at any appropriate temperature from the freezing point of the reaction mixture to the reflux point. The preferred reaction is carried out within a temperature range of from about 50 t. More preferably, it is performed in a temperature range of about 5 ° C to about 25 ° C. U.S. Patent No. 5,068,433 and related U.S. Patent No. 5,391,735 disclose that an epoxide of formula lb can be prepared from trans-cinnamyl alcohol using suitable oxidants, such as vanadic anhydride and hydrogen peroxide, or peroxy acids, such as peroxy Benzoic acid, m-chloroperoxybenzoic acid, peroxyacetic acid, mono- or di-peroxyphthalic acid, or peroxy-trifluoroacetic acid. In Example 1, these patents exemplify the preparation of an epoxide of the formula lb via oxidation of trans-cinnamyl alcohol with m-chloroperoxybenzoic acid. Oxidation of trans-cinnamyl alcohol with m • chloroperoxybenzoic acid was also proposed by P. Meloni (Tetrahedron), 19 8 5, 4 1, No. 7, 1393_1399. m-chloroperoxybenzoic acid is expensive for commercial use. Therefore, various epoxidation reagents will be preferred for compounds on a commercial scale (A). Studies with mono-peroxy-phthalic acid have shown that this reagent can be used to prepare epoxide lb on a commercial scale. However, preparing mono-peroxy-phthalic acid from phthalic anhydride and hydrogen peroxide is time consuming. In addition, the epoxidation reaction with monoperoxy-phthalic acid produces a large amount of solid phthalic acid by-product, which must be filtered from the product mixture. This laborious, time-consuming step and generate a large amount of aqueous and solid waste. Therefore, m_chloroperoxybenzoic acid and mono-peroxy-phthalic acid are not ideally suited for the commercial use of trans-cinnamyl alcohol. 15- This paper size applies to the Chinese National Standard (CNS) A4 (210 X 297 mm). " ----- -------- Order ------- (Please read the notes on the back before filling out this page) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 1238155 A7- —____ B7__ V. Description of the invention (13) Large-scale epoxidation reaction. It was found that the epoxidation of cinnamyl alcohol can be conveniently carried out on a commercial scale using peroxyacetic acid. Peracetic acid is less expensive and is a liquid, which is easier to handle on a large scale than solid chloroperoxybenzoic acid. In addition, the use of peroxyacetic acid reduces the time required to prepare epoxides by eliminating the need to prepare mono-peroxy-phthalic acid; compared to the reaction with mono_peroxy-phthalic acid, peroxyacetic acid is also quite comparable Reduces the amount of aqueous and solid waste generated by the epoxidation reaction. Therefore, the present invention provides a method for preparing an epoxide of formula Ia:

la 經濟部智慧財產局員工消費合作社印製Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs

其包括以過氧乙酸將對應之視需要取代之反式-桂皮醇氧化。裱氧化物Ia對於以強酸分解非常敏感。商用過乙酸係、瓜酸士足化。因此，過氧乙酸在使用前應該以一種適當 =處理（例如乙酸鈉或鉀）；或者反應能夠便利地在適當田體鹼存在下榛作（例如碳酸納或鉀）。較佺反應係以商業模進仃。較佳反應係在二氯甲烷中且在溫.度低於約3〇°C 行。與化學式la之環氧化物與適需要取代之苯酚反應，得到子式11 a之一醇的反應能夠使用適當鹼而便利地進行，例氧化鋼或鉀’氫化鈉，或氫化_。反應能夠在任 2田/谷劑或溶劑組合物中進行，例如烴，自化烴，或 ’支鏈醚’如苯，甲苯，四氫呋喃，二氣曱烷，L 固規進化例直乙 -------------------訂--------- (請先閱讀背面之注意事項再填寫本頁) 本紙張尺度賴 -16- 297公釐）This includes the oxidation of the corresponding, if necessary, trans-cinnamyl alcohol with peracetic acid. Mounting oxide Ia is very sensitive to decomposition by strong acids. Commercial peracetic acid series, citrulic acid foot. Therefore, peroxyacetic acid should be treated with an appropriate treatment (such as sodium or potassium acetate) before use; or the reaction can be conveniently made in the presence of an appropriate alkaloid (such as sodium or potassium carbonate). The comparative response is based on a commercial model. The preferred reaction is in dichloromethane and at a temperature below about 30 ° C. The reaction with an epoxide of the chemical formula la with an optionally substituted phenol to obtain an alcohol of the sub-formula 11a can be conveniently performed using a suitable base, such as steel oxide or potassium 'sodium hydride, or hydrogenation. The reaction can be performed in any field / cereal or solvent composition, such as hydrocarbons, self-chemical hydrocarbons, or 'branched ethers' such as benzene, toluene, tetrahydrofuran, dioxane, and L solid evolution examples. ---------------- Order --------- (Please read the notes on the back before filling out this page) The paper size depends on -16-297 mm)

五、發明說明（14 ) 1238155 一圬烷。反應能夠在從反應混合物冰點至迴流溫度之任何迤當溫度進行。較佳反應係在約0°C至約100°C之溫度範園内進行。更佳係在約2(rc至約5〇χ：之溫度範圍内進 /亍較佳反應能夠在使用如實例2中所説明之適當相轉移觸媒（例如三丁甲基氯化銨）之相轉移環境下進行。 P.梅洛尼 et al·四面體，1985，41，編號7，1393_1399 揭示以再結晶將化學式Π (圖1}之化合物從異丙醚隔離。、發現化學式II之化合物能夠便利地以再結晶從曱基三級丁基醚（MTBE)隔離。MTBE較異丁醚不筇貴且較不易形成***性過氧化物。因此，化學如之化合物較佳能夠以再結晶從MTBE隔離。在化學式Ila之二醇中保護一級羥基以形成化學式nia之單-保護化合物，其中P爲矽烷基鍵聯保護基，能夠使用任何適*之矽烷化試劑進行（例如三級丁基二甲基氯化矽 ' 一甲基氯化石夕k，二級丁基二苯基氯化石夕院，三乙基鼠化石夕燒，三異丙基氣化碎燒，具有或不具三甲基氯化石夕燒之六甲基：硬氨㉟，或三苯基氯化㈣）。反應能夠在任何溶劑或溶劑組合物中進行，例如，煙，醋，自化煙，或直鏈或支鏈醚，例如苯，甲苯，氣仿，二氯甲烷，二乙醚，四氫吱喃，乙酸乙m垸。反應能夠在容許一級醇超越=級醇而選擇性保護之任何適當溫度進行，條件爲該溫度高於反應混合物之冰點。較佳反應係在低於之度進行。更佳反應係在低於_1〇π或低於之溫度進行。最佳反應係在約-15。(：至約_25。〇之溫度範圍内進本紙張尺度適用中國國家標準（CNS)A4規格（210 (請先閱讀背面之注意事項再填寫本頁)V. Description of the invention (14) 1238155 Monooxane. The reaction can be carried out at any temperature ranging from the freezing point of the reaction mixture to the reflux temperature. The preferred reaction is carried out in a temperature range of about 0 ° C to about 100 ° C. More preferably, the reaction is carried out in a temperature range of about 2 (rc to about 50 × :). The preferred reaction is capable of phase transfer using a suitable phase transfer catalyst such as tributylmethylammonium chloride as described in Example 2. Performed under environmental conditions. P. Meloni et al. Tetrahedron, 1985, 41, No. 7,1393_1399 revealed that the compound of formula II (Figure 1) was isolated from isopropyl ether by recrystallization. It was found that the compound of formula II can be conveniently It is isolated by recrystallization from fluorenyl tertiary butyl ether (MTBE). MTBE is less expensive than isobutyl ether and less likely to form explosive peroxides. Therefore, compounds that are chemically equivalent can be isolated from MTBE by recrystallization. The primary hydroxyl group is protected in a diol of the chemical formula Ila to form a mono-protected compound of the chemical formula nia, where P is a silane-linked protective group, which can be performed using any suitable silylating reagent (such as tertiary butyl dimethyl chloride) Silicone 'Monomethyl Chloride Oxygenate, Secondary Butyl Diphenyl Chloride Oxygenate, Triethyl Rat Fossil Oxygen Burn, Triisopropyl Gasification and Burning, with or without Trimethyl Chloride Oxygen Burn Hexamethyl: hard ammonia, or triphenylphosphonium chloride ). The reaction can be carried out in any solvent or solvent composition, for example, tobacco, vinegar, chemical fume, or linear or branched ether, such as benzene, toluene, aerosol, dichloromethane, diethyl ether, tetrahydrozine The reaction can be carried out at any suitable temperature that allows the primary alcohol to exceed the primary alcohol for selective protection, provided that the temperature is above the freezing point of the reaction mixture. The preferred reaction is carried out at a temperature below. More The best reaction is carried out at a temperature lower than -10 π or lower. The best reaction is carried out within a temperature range of about -15. (: To about _25. 0) This paper scale applies Chinese National Standard (CNS) A4 Specifications (210 (Please read the notes on the back before filling out this page)

經濟部智慧財產局員工消費合作社印製 -17- 1238155 A7 B7 五、發明說明（15 ) 行。其它適合之矽烷化試劑和反應環境於該技藝中已知，例如見葛林（Greene )，T. W.;伍茲（Wutz )，！>·〇· μ ” 有機合成中之保護基”第二版’ 1991，紐約，約輪威利桑斯公司（John Wiley & sons，Inc. ) 0 如圖IV中所説明，美國專利第5,〇68,433和s，3% 7S5號揭示，化學式nb之二醇能夠被酯化以得到化學式nib之化合物，其中I爲羧酸之殘基。不幸地，二醇中—級醇之保護，在這些專利中所述之環境下，係以低選擇性進行；在二級醇亦形成達13%之酯。在二級醇形成單對硝苯甲酸酉旨導致化學式VIb之胺產率直接降低。在二級醇形成單對硝苯甲酸酯亦產生化學式VIb之胺不希望之非鏡像異構物，如同胺產物中之污染物般。此外，形成雙對硝苯甲酸醋引起化學式VIb之胺產率降低，且得到如胺產物内冷染物般之雙對硝苯甲酸酯。由於這些不希望之污染物的存在，需要將胺產物廣泛地純化，其耗時且使產率額外地降低。因此，美國專利第5,068,433和5,391，735號理想上並不適於以商業規模生產化學式Via之胺。 ' 頃意外地發現在化學式lib之二醇中一級醇能夠以高產率使用矽烷基保護基選擇性地保護。尤其，頃發現—、級醇能夠以三甲矽院基選擇性地保護。在與一級醇相對於-級醇二者之反應中，與三甲氯矽烷之反應幾乎爲完全選擇性，且在無雙·三甲矽烷醚存在下。結果由本發明之方法得到之胺Vllb的產率顯著提高超越使用先前已知方法得到之產率。此外，三甲氣矽烷較對硝氯化苯甲醯不昴貴，更 ——身 (請先閱讀背面之注意事項再填寫本頁) 訂--------- 經濟部智慧財產局員工消費合作社印製 -18 -Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs -17-1238155 A7 B7 V. Description of Invention (15) OK. Other suitable silylation reagents and reaction environments are known in the art, see, for example, Greene, T. W .; Wutz ,! > · 〇 · μ "Protective Groups in Organic Synthesis" Second Edition '1991, New York, John Wiley & Sons, Inc. 0 As illustrated in Figure IV, US Patent No. 5, 〇68,433 and s, 3% No. 7S5 revealed that the diol of the chemical formula nb can be esterified to obtain the compound of the chemical formula nib, where I is a residue of a carboxylic acid. Unfortunately, the protection of secondary alcohols in diols is performed with low selectivity under the circumstances described in these patents; esters of up to 13% are also formed in secondary alcohols. The formation of mono-p-nitrobenzoate in the secondary alcohol leads to a direct reduction in the yield of the amine of formula VIb. The formation of mono-p-nitrobenzoate in a secondary alcohol also produces undesired non-mirror isomers of the amines of formula VIb, like contaminants in amine products. In addition, the formation of bis-p-nitrobenzoate causes a decrease in the yield of the amine of formula VIb, and a bis-p-nitrobenzoate is obtained as a cold dye in the amine product. Due to the presence of these undesirable contaminants, extensive purification of the amine product is required, which is time consuming and additionally reduces yields. Accordingly, U.S. Patent Nos. 5,068,433 and 5,391,735 are ideally not suitable for the commercial production of amines of the formula Via. It was unexpectedly discovered that the primary alcohols in the diols of the chemical formula lib can be selectively protected with a silyl protecting group at a high yield. In particular, it was discovered that —-grade alcohols can be selectively protected with trimethylsilicon. In the reaction with both primary alcohols and -alcohols, the reaction with trimethylchlorosilane is almost completely selective, and in the absence of bis · trimethylsilyl ether. As a result, the yield of the amine Vllb obtained by the method of the present invention is significantly improved over the yield obtained using the previously known method. In addition, trimethylsilyl is less expensive than p-nitrobenzyl chloride, and it is more important to you (please read the precautions on the back before filling this page). Order --------- Staff of Intellectual Property Bureau, Ministry of Economic Affairs Printed by Consumer Cooperatives-18-

五、發明說明（16 經濟部智慧財產局員工消費合作社印製 1238155 易於取得，JL更易於大量處理，因爲三甲基氯切貌爲液體且對硝氯化苯甲醯爲固體。在lib與二甲基氯化石夕燒之反應中存在些許選擇性之優先權。主要在希望結果爲徹底矽烷化之分析應用中，頃廣泛地使用二甲石夕祝基作爲醇類之衍生。在不同環境中二級醇之反應頃看到相當之選擇性（例如見H· j·西尼德 (Schneider) ’ R·宏寧（Horning)，Leibigs Ann· Chem·， 1974，1864_1871和£1•洋基（Yankee) et al，了 —以咖 Soc·，1974 , 5865)。然而，關於一級和二級醇反應之相關速率資訊並不可得，文獻缺乏在二級醇存在下，以三甲基氯化碎燒選擇性保護一級醇之實例。在二級醇存在下一級醇反應之實例經提出爲以三甲基氯化矽烷催化而與六甲基一石夕氨 fe 反應（J.寇西（Cossy)，P.佩爾（paie)，Tet. Lett 1987 ’ 603 9-6040 )，以及以金屬氯化物催化而與六甲基二石夕氨;fe反應（H·菲若莎拜迪（Firouzabadi)，et al.，Syn Comm.，1997，2709-2719)，其中最佳選擇性爲 85:3· 12，一級：二級：雙醚）。一級醇之選擇性保護能夠在低溫使用碎燒保護基（較佳爲二甲基氯化石夕燒）完成。亦頃測定碎燒保護基之移動能夠藉由1 )在從化學式Ila之化合物轉變爲化學式v a之化合物期間將化學式Ilia之保護化合物維持於低溫，和2 )以短期間進行需要之反應序列（例如較其少5小時，且較佳少約4，約3，或約2小時）而避免。如實例6中所説明般，此能夠便利地藉由在一個反應器中進行將化學式Ila之二醇 -19- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐）V. Description of the invention (16 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 1238155 Easy to obtain, JL is easier to handle in large quantities, because trimethyl chloride is liquid and p-nitrobenzyl chloride is solid. There is a slight selectivity priority in the reaction of methyl chlorinated stone. Mainly in analytical applications where the result is expected to be completely silylated, dimethyxyl is widely used as a derivative of alcohols. In different environments The reaction of secondary alcohols has seen considerable selectivity (see, for example, Schneider's R. Horning, Leibigs Ann. Chem., 1974, 1864_1871, and £ 1. Yankee ) et al, Yi-Ic Soc ·, 1974, 5865). However, information on the rate of reaction between primary and secondary alcohols is not available, and the literature lacks the use of trimethyl chloride in the presence of secondary alcohols. Examples of selective protection of primary alcohols. Examples of reactions of primary alcohols in the presence of secondary alcohols have been proposed as reactions with hexamethyl-monomethylamine in the presence of trimethylsilyl chloride (J. Cossy, P Paie, Tet. Lett 1987 603 9-6040), and the reaction with hexamethyldistilbene amine catalyzed by metal chloride (H. Firouzabadi, et al., Syn Comm., 1997, 2709-2719) Among them, the best selectivity is 85: 3 · 12, first grade: second grade: diether). Selective protection of primary alcohols can be accomplished at low temperatures using a calcined protective group (preferably dimethyl chloride stone fired). It is also determined that the movement of the crushed protective group can be achieved by 1) maintaining the protective compound of formula Ilia at a low temperature during the transition from a compound of formula Ila to a compound of formula va, and 2) performing the required reaction sequence in a short period of time (eg 5 hours less, and preferably about 4, 3, or 2 hours less) to avoid. As illustrated in Example 6, this can be conveniently carried out in a reactor by the diol of the chemical formula Ila -19- This paper size applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm)

1238155 A7 B7 五、發明說明（17 ) 轉變爲化學式Ilia，IVa和Vai化合物而完成，未將化學式Ilia，IVa之中間體隔離。因此，本發明提供化學式Ilia之製備方法：1238155 A7 B7 V. Description of the invention (17) The conversion to the compounds of the formula Ilia, IVa and Vai is completed, and the intermediates of the formula Ilia, IVa are not isolated. Therefore, the present invention provides a preparation method of the chemical formula Ilia:

其中P爲矽烷基鍵聯反應基；其包括將化學式IIa之適當之矽烷化試劑反應：二醇與Where P is a silane-based reactive group; it includes reacting a suitable silylating agent of formula IIa: a diol with

(Ri)ni 經濟部智慧財產局員工消費合作社印製較佳P爲三曱矽烷基，該矽烷化試劑爲三甲基氯化矽烷。較佳溶劑包括乙酸乙酯和二氯甲烷。化學式Ilia之醇類與磺酸之反應性衍生物反應，得到其中R a爲磺酸殘基之化學式IVa化合物之反應能夠使用任何適當之磺基化試劑進行，例如，磺酸鹵化物，尤指磺酸氯化物（例如對甲苯續醯氯，苯磺醯氯，（CVC6)烷基磺醯氯，或三氟甲基磺醯氯）。一種磺酸之較佳反應性衍生物爲甲烷磺醯氣。反應能夠便利地在適當鹼存在下進行（例如三乙胺或峨淀）。反應能夠在任何適當溶劑或溶劑組合 -20- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） ----------------I---- 麗訂·--------線 (請先閱讀背面之注音？事項再填寫本頁) 1238155 A7 B7 五、發明說明（ 18 經濟部智慧財產局員工消費合作社印製物中進行，例如烴，鹵化煙，有機醋，或直鍵或支缝醚，例如苯，甲苯，四氫呋喃，二氯甲烷，乙酸乙酯，二乙醚，或二吟烷。反應較佳在乙酸乙酯中進行。反應能夠在任何高於反應混合物冰點之溫度進行。較佳反應係在低於-5°C之溫度進行。更佳反應係在低於-i〇°c或低於-15。〇之溫度進行。最佳反應係在約-15°C至約-25°C之溫度範圍内進行。其它適合之磺酸反應性衍生物和反應環境於該技藝中已知，例如見傑立馬區（jerry March )，，進階有機化學” 第四版，I"2，紐約，約翰威利桑斯公司，352-356。從化學式IVa之化合物移除矽烷基以得到化學式v a之醇能夠使用任何適當觸媒進行，例如酸（例如HC1)或氟化物離子來源（例如四丁基氟化銨）。反應能夠在任何適當溶或溶劑組合物中進行，例如烴，南化烴，有機酯，或直或支鏈醚，例如苯，甲苯，氯仿，二氯甲烷，乙酸乙酯二***，四氫呋喃，或二吟烷。反應較佳在乙酸乙酯中行。反應能夠在任何高於反應混合物冰點之溫度進行。佳反應係在約-78t：至約loot：之溫度範圍内進行。更佳應係在約-5 0 C至約5 0 〇Γ* 土、、四淨f 。王L ，皿度範圍進衧。最佳反應係約-25°C至約25。(：之溫度範圍内進行。化學式Va之醇類反應以得到化學式via 應何適當驗存在下進行，例如類似氯氧化二或溶劑_中進行，例二醚，例如苯，甲苯，氯仿，二一鏈乳T /兀’ 一***，四氫呋劑進較反在 -21-(Ri) ni Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs. P is preferably trimethylsilyl, and the silylating agent is trimethylsilyl chloride. Preferred solvents include ethyl acetate and dichloromethane. The reaction of alcohols of formula Ilia with reactive derivatives of sulfonic acids to obtain compounds of formula IVa in which R a is a sulfonic acid residue can be performed using any suitable sulfonating reagent, for example, sulfonated halides, especially Sulfonic acid chlorides (such as p-toluene chloride, benzenesulfonium chloride, (CVC6) alkylsulfonium chloride, or trifluoromethylsulfonium chloride). A preferred reactive derivative of sulfonic acid is methanesulfonium. The reaction can conveniently be carried out in the presence of a suitable base (e.g. triethylamine or Edo). The reaction can be performed in any suitable solvent or solvent combination. -20- This paper size applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm) ---------------- I-- -Li Ding · -------- line (please read the note on the back? Matters before filling out this page) 1238155 A7 B7 V. Description of the invention (18 Printed in the printed consumer cooperative of employees of the Intellectual Property Bureau of the Ministry of Economic Affairs , Such as hydrocarbons, halogenated fumes, organic vinegar, or straight or branched ethers, such as benzene, toluene, tetrahydrofuran, dichloromethane, ethyl acetate, diethyl ether, or dioxane. The reaction is preferably performed in ethyl acetate. The reaction can be performed at any temperature above the freezing point of the reaction mixture. The preferred reaction is performed at a temperature below -5 ° C. The more preferred reaction is at a temperature below -100 ° C or below -15 ° C. The optimal reaction is carried out at a temperature range of about -15 ° C to about -25 ° C. Other suitable sulfonic acid-reactive derivatives and reaction environments are known in the art, see, for example, jerry March), "Advanced Organic Chemistry" Fourth Edition, I " 2, New York, John Willisance Corporation, 352-356. From Chemistry The removal of the silyl group of the compound of formula IVa to give the alcohol of formula va can be performed using any suitable catalyst, such as an acid (such as HC1) or a fluoride ion source (such as tetrabutylammonium fluoride). The reaction can be carried out at any suitable solvent or It is carried out in a solvent composition, such as a hydrocarbon, a sulfonated hydrocarbon, an organic ester, or a straight or branched chain ether, such as benzene, toluene, chloroform, dichloromethane, ethyl acetate diethyl ether, tetrahydrofuran, or dioxane. The reaction is preferred It is carried out in ethyl acetate. The reaction can be carried out at any temperature higher than the freezing point of the reaction mixture. The best reaction is carried out in a temperature range of about -78t: to about loot :. More preferably, it should be about -50C to about 5 0 〇Γ * Earth, Si, net f. Wang L, the range of the degree of 衧. The best reaction is about -25 ° C to about 25. (: temperature range. Chemical reaction of alcohols of formula Va to get the chemical formula Via should be performed in the presence of appropriate tests, such as chlorinated dioxin or in solvents, such as diethers, such as benzene, toluene, chloroform, diene chain milk T / Wu 'monoethyl ether, tetrahydrofuran agent is more effective -twenty one-

(請先閱讀背面之注意事項再填寫本頁) -fl— i n mmmMMm an MOB ^ ^ I 1 Hi emmmt t§ ·"0 #. 1238155(Please read the notes on the back before filling this page) -fl— i n mmmMMm an MOB ^ ^ I 1 Hi emmmt t§ · " 0 #. 1238155

五、發明說明（19 請先閱讀背 Si 之注意事項填本頁 ’或二嘮烷。反應較佳在適當相轉移觸媒（如三丁基甲基氣化銨）存在下，在甲苯和水之混合物中於相轉移環境下進行。反應能夠在任何高於反應混合物冰點且低於迴流之溫度進行。較佳反應係在約-78°C至約1〇〇。(3之溫度範圍内進行。更佳反應係在低於約-5(rc至約50。〇之溫度範圍進行。最佳反應係在約15°c至約30°c之溫度範圍内進行。如圖I V中所説明，美國專利第5,〇68,433和5,391，735號揭tf ’化學式lvb之化合物能夠藉由在水性有機溶劑中，例如二4烷或二甲基甲醯胺（見其中實例5，第*楙第19 — 27行）’以適當鹼處理而轉變爲化學式Vb之環氧化物。p . 梅洛尼et al·四面體，1985，41，編號7，1393-1399亦揭不化學式IVb之特定化合物經由在二嘮烷中以氫氧化鈉處理而轉變爲化學式vb之對應環氧化物（見第1397頁）。當以大規模（約1 6 5公斤）進行時，此反應緩慢（i 8小時）且由於其高沸點和高冰點（mp )，難以移除二嘮烷。因此，蒸餾能夠需要一至二天，且在蒸餾期間存在二呤烷將在裝置内結冰的風險，其引起對於冷凝器之傷害。此外，二嘮烷具謗癌性且毒性。經濟部智慧財產局員工消費合作社印製如圖II中所説明，且如以下實例6中所示般，頃發現化學式va之化合物能夠在相轉移環境下，於甲苯和水之混合物中轉變爲化學式VIa之環氧化物。反應能夠以約45分鐘大規模進行，甲苯能夠簡單地從產物混合物移除。因此，本發明提供一種化學式Via化合物之製備方法： -22- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公爱） 1238155 A7 B7 五、發明說明（20 (R)n -σ: 〇xM3~(R,)n,V. Explanation of the invention (19 Please read the precautions for Si first and fill in this page 'or dioxane. The reaction is preferably in the presence of a suitable phase transfer catalyst (such as tributylmethyl ammonium gasification) in a mixture of toluene and water The reaction can be carried out in a phase transfer environment. The reaction can be performed at any temperature higher than the freezing point of the reaction mixture and lower than the reflux temperature. The preferred reaction is performed at a temperature range of about -78 ° C to about 100. (3). The best reaction is performed at a temperature range of less than about -5 ° C to about 50 ° C. The best reaction is performed at a temperature range of about 15 ° c to about 30 ° c. As illustrated in Figure IV, the US patent Nos. 5,068,433 and 5,391,735 disclose that the compounds of the chemical formula lvb can be used in aqueous organic solvents such as dioxane or dimethylformamide (see Example 5, No. 19 * 27). (Line) 'treated with an appropriate base to convert to an epoxide of formula Vb. P. Melone et al. Tetrahedron, 1985, 41, number 7, 1393-1399 also reveals that certain compounds of formula IVb do not pass through Treated with sodium hydroxide in alkane to convert to the corresponding epoxy of chemical formula vb (See page 1397). When carried out on a large scale (approximately 165 kg), this reaction is slow (i 8 hours) and due to its high boiling point and high freezing point (mp), dioxane is difficult to remove. Therefore Distillation can take one to two days, and there is a risk that the diuridine will freeze in the device during the distillation, which will cause damage to the condenser. In addition, the dioxane is defamatory and toxic. Employees of the Intellectual Property Bureau of the Ministry of Economic Affairs The consumer cooperative printed as illustrated in Figure II, and as shown in Example 6 below, it was found that the compound of formula va can be converted to the epoxide of formula VIa in a mixture of toluene and water under a phase transfer environment. The reaction can be carried out on a large scale in about 45 minutes, and toluene can be simply removed from the product mixture. Therefore, the present invention provides a method for preparing a compound of the formula Via: -22- This paper size is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 public love) 1238155 A7 B7 V. Description of the invention (20 (R) n -σ: 〇xM3 ~ (R,) n,

Vra 其中R，Ri，n和η 1具有此處所定義之任何數値；其包括在相轉移環境下以適當鹼處理化學式V a之對應化合物:Vra wherein R, Ri, n and η 1 have any number defined herein; it includes treating the corresponding compound of formula V a with a suitable base under a phase transfer environment:

經濟部智慧財產局員工消費合作社印製其中Ra爲磺酸之殘基。較佳反應係在約〇°C至約反應混合物之迴流溫度之溫度範圍内進行。反應更佳係在約i 5〇C至約35°C之溫度範圍内進行。化學式Via之環氧化物與氨反應以得到化學式VIIa胺之反應能夠在任何適當氨來源存在下進行，例如水性氨或< 氧化銨。反應能夠在任何適當溶劑或溶劑組合物中進行，例如烴，鹵化烴，脂肪族醇或直鏈或支鏈醚，例如苯，曱苯，氯仿，二氯甲烷，二***，甲醇，乙醇，異丙醇，一呤烷，四氫呋喃，或二甲基甲醯胺。反應較佳在甲醇中使用氫氧化铵作爲氣來源進行，如實例7中所述般。反應夠在反應混合物迴流溫度或低於該溫度之任何溫度進<一' 厶匕月匕 --------------------"訂·-------- (請先閱讀背面之注音？事項再填寫本頁} -23- 1238155Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs where Ra is the residue of a sulfonic acid. The preferred reaction is carried out at a temperature ranging from about 0 ° C to about the reflux temperature of the reaction mixture. The reaction is more preferably performed at a temperature ranging from about 50 ° C to about 35 ° C. The reaction of the epoxide of formula Via with ammonia to give the amine of formula VIIa can be carried out in the presence of any suitable source of ammonia, such as aqueous ammonia or < ammonium oxide. The reaction can be carried out in any suitable solvent or solvent composition, such as a hydrocarbon, a halogenated hydrocarbon, an aliphatic alcohol or a linear or branched chain ether, such as benzene, toluene, chloroform, dichloromethane, diethyl ether, methanol, ethanol, isopropyl alcohol. Propanol, monopyrane, tetrahydrofuran, or dimethylformamide. The reaction is preferably carried out in methanol using ammonium hydroxide as a gas source, as described in Example 7. The reaction is sufficient at the reflux temperature of the reaction mixture or at any temperature lower than that temperature. ------ (Please read the Zhuyin on the back? Matters before filling out this page} -23- 1238155

經濟部智慧財產局員工消費合作社印製五、發明說明（21 ) 較佳反應係在約-50C至約10{rc之溫度範圍内進行。更佳反應係在低於約0°c至約80。(：之溫度範圍進行。最佳反應係在約2 0 C至約5 0 C之溫度範圍内進行。、化學式Vila之胺反應以得到化學式¥11]^之對應醯胺之反應能夠便利地與化學式HOOCCHA之羧酸反應性衍生物進行，其中L爲一種適當離去基。適當之離去基於該技藝中已知，且包括自化物（例如溴，氯，或碘），磺醯酯（例如 4 -甲苯磺醯氧基，甲基磺醯氧基，三氟甲基磺醯氧基， (C^-C6)燒基續醯氧基，或苯基磺醯氧基，其中苯基可以視需要以一個或多個獨立擇自鹵基，（Ci-c6)烷基，硝基，（CyC6)烷氧基，三氟甲基，和氰基）之取代基取代。一種較佳之羧酸爲氯乙醯氯。反應能夠便利地在任何適當鹼存在下進行（如三乙胺或吡啶）。反應能夠在任何適當溶劑或溶劑組合物中進行，例如烴，_化烴，有機酯，或直鏈或支鏈醚，例如苯，甲苯，氣仿’二氯甲烷，乙酸乙酯，碳酸甲酯，二***，四氫呋喃，或二崎烷。反應較佳在碳酸甲酯或二氯甲烷中進行。反應能夠在任何高於反應混合物冰點之溫度進行。較佳反應係在低於50°C之溫度進行。更佳反應係在低於25。〇或低於15 C之溫度進行。最佳反應係在約至約丨〇。〇之溫度範圍内進行。化學式Villa之化合物反應以形成化學式IXa嗎啉酮之反應能夠便利地在一種適當鹼存在下進行（例如氫化鈉，氫化鉀’或二級丁氧化鉀）。反應能夠在任何適當溶劑或溶 -24- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公爱） --^------------ -----訂·---I---- (請先閱讀背面之注意事項再填寫本頁) χ238ΐ55Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs. 5. Description of the Invention (21) The preferred reaction is performed at a temperature range of about -50C to about 10 {rc. A more preferred reaction is between about 0 ° C and about 80 ° C. (: In the temperature range. The optimal reaction is carried out in the temperature range of about 20 C to about 50 C.) The reaction of the amine of the chemical formula Vila to obtain the chemical reaction of the corresponding hydrazine can be conveniently performed with A carboxylic acid-reactive derivative of the chemical formula HOOCCHA is performed, where L is a suitable leaving group. Suitable leaving is based on known techniques and includes autologous compounds (such as bromine, chlorine, or iodine), sulfonyl esters (such as 4-toluenesulfonyloxy, methylsulfonyloxy, trifluoromethylsulfonyloxy, (C ^ -C6) alkylsulfonyloxy, or phenylsulfonyloxy, where phenyl can be visualized Substitution with one or more substituents independently selected from halo, (Ci-c6) alkyl, nitro, (CyC6) alkoxy, trifluoromethyl, and cyano) is preferred. A preferred carboxylic acid is Chloroacetamidine. The reaction can be conveniently carried out in the presence of any suitable base (such as triethylamine or pyridine). The reaction can be carried out in any suitable solvent or solvent composition, such as a hydrocarbon, alkylated hydrocarbon, organic ester, or Chain or branched chain ethers, such as benzene, toluene, gas-formed dichloromethane, ethyl acetate, methyl carbonate Diethyl ether, tetrahydrofuran, or diazane. The reaction is preferably carried out in methyl carbonate or dichloromethane. The reaction can be carried out at any temperature above the freezing point of the reaction mixture. The preferred reaction is carried out at a temperature below 50 ° C. A more preferred reaction is carried out at a temperature of less than 25.0 or less than 15 C. The best reaction is carried out at a temperature ranging from about to about 0.00. The compound of the chemical formula Villa reacts to form a morpholinone of the chemical formula IXa. The reaction can be conveniently carried out in the presence of a suitable base (such as sodium hydride, potassium hydride 'or secondary potassium butoxide). The reaction can be performed in any suitable solvent or solvent-24- This paper applies Chinese National Standard (CNS) A4 Specifications (210 X 297 public love)-^ ------------ ----- Order · --- I ---- (Please read the precautions on the back before filling this page ) χ238ΐ55

經濟部智慧財產局員工消費合作社印製劑組合物中進行，例如M，南化M ’脂膀族醇，或直鍵或支鏈醚，例如苯，甲苯，二氯甲烷，二***，異丙醇，四氫呋喃，或二吟烷。反應較佳在異丙醇中以三級丁氧化奸作爲鹼而進行，如實例9中所述般。反應能夠在任何高於反應混合物冰點且爲混合物迴流溫度或低於該溫度之溫度進行。較佳反應係在低於約_78。(：至約1〇(rc之溫度範:二進行。更佳反應係在約-25Ό至約50X：之溫度範圍進行。最佳反應係在約〇°C至約30°C之溫度範圍内進行。化學式IXa之嗎啉酮形成化學式（A)，其中1和1爲乙烯之化合物的還原反應能夠便利地在適當還原劑存在下進行 (如甲硼烷，氫化鋰銨，二異丁基氫化銨，二異丙基氯化銨，或雙（2-甲氧乙氧）氫化銨鈉）。反應能夠在任何適當溶劑或溶劑組合物中進行，例如烴，或直鏈或支鏈醚，例如苯，甲苯，二***或四氫呋喃。反應能夠在任何高於反應混合物冰點和混合物迴流溫度或低於該溫度之溫度進行。較佳反應係在低於約-78°C至約l〇(TC之溫度範圍内進行。更佳反應係在低於50°C之溫度或在低於i〇°C之溫度進行。最佳反應係在約-20°C至約5°C之溫度範圍内進行。 P.梅洛尼et al·四面體，1985，41，編號7，1393-1399，於第1外9頁，揭示化學式IX (圖I)之嗎啉酮能夠藉由將含2.96當量之REDAL (雙（2-甲氧乙氧）氫化銨鈉）之曱苯溶液添加於嗎啉酮溶液而還原爲對應嗎啉 (Reboxetine ) 0 當此反應係以大規模進行行時（約2 5公斤嗎琳酮），反應 -25- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） ----------------- (請先閱讀背面之注意事項再填寫本頁) 1238155Employees of the Intellectual Property Bureau of the Ministry of Economic Affairs in the consumer cooperative printing preparation composition, such as M, Nanhua M 'aliphatic alcohols, or linear or branched ethers, such as benzene, toluene, dichloromethane, diethyl ether, isopropyl alcohol , Tetrahydrofuran, or dioxane. The reaction is preferably carried out in isopropanol using tertiary butoxide as a base, as described in Example 9. The reaction can be carried out at any temperature above the freezing point of the reaction mixture and at the reflux temperature of the mixture or below this temperature. The preferred reaction is below about -78. (: To about 10 (rc temperature range: 2). The better reaction is carried out at a temperature range of about -25 ° to about 50X :. The best reaction is in a temperature range of about 0 ° C to about 30 ° C. The morpholinone of chemical formula IXa forms chemical formula (A), in which the reduction reaction of compounds in which 1 and 1 are ethylene can be conveniently performed in the presence of a suitable reducing agent (such as borane, lithium ammonium hydride, diisobutyl hydrogenation). Ammonium, diisopropylammonium chloride, or sodium bis (2-methoxyethoxy) ammonium hydride). The reaction can be performed in any suitable solvent or solvent composition, such as a hydrocarbon, or a linear or branched ether, such as Benzene, toluene, diethyl ether or tetrahydrofuran. The reaction can be performed at any temperature above the freezing point of the reaction mixture and the reflux temperature of the mixture or below this temperature. The preferred reaction is at a temperature of about -78 ° C to about 10 ° C It is carried out in a temperature range. A more preferable reaction is carried out at a temperature lower than 50 ° C or a temperature lower than 10 ° C. The optimal reaction is carried out at a temperature range of about -20 ° C to about 5 ° C. P. Meloni et al. Tetrahedron, 1985, 41, No. 7, 1393-1399, on page 1, outside 9, unveiled The morpholinone of chemical formula IX (Figure I) can be reduced to the corresponding morpholinone by adding a toluene solution containing 2.96 equivalents of REdal (sodium bis (2-methoxyethoxy) ammonium hydride) to the morpholinone solution ( Reboxetine) 0 When this reaction is carried out on a large scale (approximately 25 kg of morphinone), the reaction is -25- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) ---- ------------- (Please read the notes on the back before filling out this page) 1238155

五、發明說明（23 ) 產物典型上受〇·6至1%以下雜質之冷染V. Description of the invention (23) The product is typically cold-stained by impurities from 0.6 to 1%

H 爲了化學式（A)之最終藥物產物符合某些國家之規定，最終產物中此雜質之濃度必需低於〇1%。移除此雜質是困難的，但能夠使用控制於約ρΗ 5·2之控制pΗ萃取而完成。然而，在此萃取期間，典型上損失2〇_3〇%化學式（A) 之化合物，且不能夠即時回收。頃測疋緣.自還原之雜質量能夠藉由將嗎琳酮Ιχ&溶液添加於含過量（如約5當量）雙（2_甲氧乙氧）氫化銨鈉之溶液而顯著降低。使用此步驟，頃發現反應直接產生含低於於〇· 1%雜質之無鹼Reb〇xetine。能夠直接使用此材料，不需進行控制pH萃取。此降低:操作時間並刪減20_3〇%之產物損耗。頃發現使用低於5當量還原劑降低反應之產率。因此，反應較佳使用至少4當量雙（2-甲氧乙氧)氫化銨鈉，或另適當還原劑而進行。反應更佳係使用至少5當量適當還原劑（例如至少約5至約1 〇當量雙（2-甲氧乙氧）氫化銨銅）而進行。最佳該還原劑並非氫化銨鋰。因此，本發明提供以下化學式之化合物的製備方法： -26- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） --------1—------- (請先閱讀背面之注意事項再填寫本頁)H In order for the final drug product of formula (A) to meet the requirements of some countries, the concentration of this impurity in the final product must be less than 0%. Removal of this impurity is difficult, but can be accomplished using controlled pΗ extraction controlled at about ρΗ 5 · 2. However, during this extraction, 20-30% of the compound of formula (A) is typically lost and cannot be recovered immediately. The amount of self-reduced impurities can be significantly reduced by adding a solution of morphinone Ιχ & to a solution containing an excess (such as about 5 equivalents) of sodium bis (2-methoxyethoxy) ammonium hydride. Using this step, it was found that the reaction directly produced alkali-free Reboxetine containing less than 0.1% impurities. This material can be used directly without the need for controlled pH extraction. This reduction: operating time and product loss of 20-30%. It was found that the use of less than 5 equivalents of reducing agent reduced the yield of the reaction. Therefore, the reaction is preferably carried out using at least 4 equivalents of sodium bis (2-methoxyethoxy) ammonium hydride, or another suitable reducing agent. The reaction is more preferably carried out using at least 5 equivalents of a suitable reducing agent (for example, at least about 5 to about 10 equivalents of copper bis (2-methoxyethoxy) ammonium hydride). Most preferably, the reducing agent is not lithium ammonium hydride. Therefore, the present invention provides a method for preparing the compounds of the following chemical formulas: -26- The paper size is applicable to China National Standard (CNS) A4 (210 X 297 mm) -------- 1 —----- -(Please read the notes on the back before filling this page)

EtOEtO

經濟部智慧財產局員工消費合作社印製 1238155 A7 ~~—--— B7 五、發明說明（24 ) II斗(_ (R)n 其中R ’ Ri，η和η 1具有任何此處定義之數値；其包括將化學式Xla之對應化合物：Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 1238155 A7 ~~ ------ B7 V. Description of the invention (24) II bucket (_ (R) n where R 'Ri, η and η 1 have any of the numbers defined here値; it includes the corresponding compound of formula Xla:

(Ri )n 1 IXa 添加於包括至少4當量適當還原劑之溶液本發明亦提供化學式Ilia之化合物： (請先閱讀背面之注咅？事項再填寫本頁) --------訂— 經濟部智慧財產局員工消費合作社印製(Ri) n 1 IXa is added to a solution including at least 4 equivalents of an appropriate reducing agent. The present invention also provides a compound of the formula Ilia: (Please read the note on the back? Matters before filling out this page) -------- Order — Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs

(Rl)nl 其中R ’ Ri，n和η 1具有任何此處對於化學式（A)之化合物中對應反應基所定義之數値，特定値或較佳値，且P爲一種適當矽烷保護基（例如三級丁基二甲矽烷基，三曱矽烷基，三級丁基二苯矽烷基，三乙矽烷基，三異丙矽烷 -27- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 1238155 A7(Rl) nl wherein R ′ Ri, n and η 1 have any number 此处, specific 値 or better 値 defined herein for the corresponding reactive group in the compound of formula (A), and P is a suitable silane protecting group ( For example, tertiary butyldimethylsilyl, tristilylsilyl, tertiary butyldiphenylsilyl, triethylsilyl, and triisopropylsilane-27- This paper is in accordance with China National Standard (CNS) A4 (210 X 297 mm) 1238155 A7

五、發明說明（25 ) 經濟部智慧財產局員工消費合作社印製土 ’三苯矽烷基）。較佳化學式IIIa之化合物爲化學式m 之化合物。本發明亦提供化學式IVa之化合物：V. Description of the invention (25) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs ("triphenylsilyl"). A preferred compound of formula IIIa is a compound of formula m. The invention also provides compounds of formula IVa:

其中R，I，η和η 1具有任何此處對於化學式（a )之化合物中對應民應基所定義之數値，特定値或較佳値，且p爲一種適當矽烷保護基（例如三級丁基二甲矽烷基，三甲石夕燒基，三級丁基二苯矽烷基，三乙矽烷基，三異丙矽烷基’ —基），且R a爲故之殘基（例如對甲苯基’苯確g盛基，甲續醯基，乙橫酿基，或三氟甲續醯基。較佳化學式IVa之化合物爲化學式I V之化合物。本發明亦提供化學式Va之化合物：Where R, I, η, and η 1 have any number defined herein for the corresponding ethene in the compound of formula (a), a specific 値 or better 値, and p is a suitable silane protecting group (eg, tertiary Butyldimethylsilyl, trimethylsilyl, tertiary butyldiphenylsilyl, triethylsilyl, triisopropylsilyl'-yl), and Ra is a residue (such as p-tolyl) 'Benzenyl, stilbene, stilbene, stilbene, or trifluorostilbene. Preferred compounds of formula IVa are compounds of formula IV. The present invention also provides compounds of formula Va:

其中R，Ri，η和η 1具有任何此處對於化學式（A)之化 -28- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） ---------—--------訂--------- (請先閱讀背面之注意事項再填寫本頁) 1238155 A7 ______B7__ 五、發明說明（26 ) 合物中對應反應基所定義之數値，特定値或較佳値，且 Ra爲續酸之殘基（例如對甲苯磺醯基，苯磺醯基，甲續酿基，乙磺醯基，或三氟甲磺醯基。較佳化學式Va之化合物爲化學式V之化合物。如圖I中所説明，本發明亦較佳提供一種化學式νπ之化合物的製備方法：Among them, R, Ri, η and η 1 have any of the chemical formula (A) here -28- This paper size applies Chinese National Standard (CNS) A4 specification (210 X 297 mm) -------- --------- Order --------- (Please read the notes on the back before filling out this page) 1238155 A7 ______B7__ V. Description of the invention (26) Corresponding reaction group in the compound The number of definitions 値, specific 値 or better 値, and Ra is a residue of a continuous acid (e.g. p-toluenesulfonyl, benzenesulfonyl, methylsulfonyl, ethylsulfonyl, or trifluoromethanesulfonyl) The preferred compound of formula Va is a compound of formula V. As illustrated in Figure I, the present invention also preferably provides a method for preparing a compound of formula νπ:

VII 服2 其包括：狂）將視需要取代之反式桂皮醇氧化，得到化學式J之中間體環氧化物： (請先閱讀背面之注意事項再填寫本頁)VII service 2 includes: Madness) Oxidation of trans-cinnamyl alcohol as needed to obtain intermediate epoxide of formula J: (Please read the precautions on the back before filling this page)

經濟部智慧財產局員工消費合作社印製 b )將該環氡化物與視需要取代之苯酚反應，得到化學式II之二醇··Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs b) Reaction of the cyclized compound with phenol substituted as needed to obtain a diol of formula II ...

-29- 本紙張尺度適用中國國家標準（CNS)A4規格（210 χ 297公釐） OEt-29- This paper size is in accordance with China National Standard (CNS) A4 (210 χ 297 mm) OEt

1238155 …/ A7 __B7_ 五、發明說明（27 ) e ) 將該二醇與矽烷化試劑反應，得到化學式III之醇：1238155… / A7 __B7_ 5. Description of the invention (27) e) The diol is reacted with a silylating agent to obtain an alcohol of formula III:

d ) 將化學式III之醇與磺酸之反應性衍生物反應，得到化學式IV之化合物：d) reacting an alcohol of formula III with a reactive derivative of a sulfonic acid to obtain a compound of formula IV:

e ) 將三甲碎燒基從化學式IV之化合物移除，得到化學式V之醇： (請先閱讀背面之注意事項再填寫本頁) -—----訂--------- αe) Remove the trimethyl sulfonyl group from the compound of chemical formula IV to obtain the alcohol of chemical formula V: (Please read the precautions on the back before filling this page) --------- Order --------- α

經濟部智慧財產局員工消費合作社印製 V 〇H f) 將磺氧基取代，得到化學式VI之環氧化物：Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs, V 〇H f) Substitute the sulfoxy group to obtain the epoxide of formula VI:

1238155 A7 B7 五、發明說明（28 ) 且物 g)將該壞氧化物與氨反應，得到化學式νπ之化人所產生化學式VII之化合物能夠便利地藉由轉變爲甲烷磺酸鹽而隔離，如實例7中所述般。凡以上化學式VII化合物之製備方法能夠視需要更包括： h)將化學式VII之化合物與氯乙醯氯反應，得到化學式VIII之醯胺^ ^ ^ ^ ^ ^ ^ ^ 子 OEt1238155 A7 B7 V. Description of the invention (28) and the substance g) react the bad oxide with ammonia to obtain the compound of formula VII produced by the chemical formula νπ can be conveniently isolated by conversion to methane sulfonate, such as As described in Example 7. Where necessary, the preparation method of the compound of the above formula VII can further include: h) reacting the compound of the formula VII with chloroacetamidine to obtain the amidine of the formula VIII ^ ^ ^ ^ ^ ^ ^ ^

N、 γ-α . VIII 〇 i)將化學式VIII之化合物反應，得到化學式Ιχ之化合物反應： _! — ！ — ！♦ (請先閱讀背面之注意事項再填寫本頁) 訂--- 經濟部智慧財產局員工消費合作社印製N, γ-α. VIII 〇 i) Reaction of the compound of the formula VIII to obtain the compound of the formula Iχ reaction: _! —! —! ♦ (Please read the notes on the back before filling out this page) Order --- Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs

且 j) 將化學式IX之化合物還原，得到以下化學式之對應嗎啉化合物： -31- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐）線# 1238155And j) reducing the compound of the chemical formula IX to obtain the corresponding morpholine compound of the following chemical formula: -31- This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) Line # 1238155

OlZtOlZt

現將藉由以下非限制性實例説明本發明，其中除非特別敘述： a)在布奇（Buchi)溶點裝置中於毛細管内測定溶定並未經校正； b )於以400· 13 MHz操作以觀察1η和於1〇〇 a ΜΗζ操作以觀察13C之布魯克（Bruke0 ΑΜΧ400上記錄NMR光譜數據；將樣品溶於内部參照CDC13 ( 4 d =7.26 ; 13C，ί = 77.0); c) 於以電子衝擊（ΕΙ)或化學離子化（CI)模式操作之費生司翠歐（Fisons Trio ) 2000單一 qU〇drupole光譜計上得到質譜數據；CI之掃描範圍爲li〇_600 amu且EI爲45_6〇〇 anm ;來源溫度爲i5〇°C，電子擴大器400 V，電子能量、7〇 eV ;以氨作爲試劑氣體進彳:^化學離子化並調整至〗4 χ 1()_4 毫托耳之來源壓力； d) 使用佩金艾瑪（Perkin Elmer) HPLC (200系列幫浦和235C二極管矩陣偵檢器），使用尼可勒西_1〇〇 (Nucleosil-l〇〇) C-18管柱，並以水和乙腈之混合物作爲溶析液，具有或不具有添加之CFsCOOH而定期監控反應；以215毫米監控桂皮戊醇轉變爲環氧化物，其它全部以 275毫米； -32- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） ——r—-II—---------訂------------ (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製The invention will now be illustrated by the following non-limiting examples, unless specifically stated: a) determination of solubility in a capillary in a Buchi melting point device without correction; b) operation at 400 · 13 MHz Observe 1η and operate at 100a ΜΗζ to observe the NMR spectrum data of Bruker at 13C (Bruke0 AMX400; record the sample in the internal reference CDC13 (4 d = 7.26; 13C, Γ = 77.0); c) Mass spectrometry data was obtained on a Fisons Trio 2000 single qUOdrupole spectrometer operating in impact (El) or chemical ionization (CI) mode; the scan range of CI was li_600 amu and EI was 45_60. anm; source temperature is i50 ° C, electron amplifier 400 V, electron energy, 70eV; ammonia is used as reagent gas to enter: ^ chemical ionization and adjusted to 〖4 χ 1 () _ 4 millitorr source Pressure; d) using a Perkin Elmer HPLC (200 series pump and 235C diode matrix detector), using a Nicolosil-10 (Nucleosil-l00) C-18 column, and Mixture of water and acetonitrile as eluent, with or without CFsCOOH added Monitor the reaction regularly; monitor the conversion of cassia pentyl alcohol to epoxide with 215mm, and all others with 275mm; -32- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) ——r—- II —--------- Order ------------ (Please read the precautions on the back before filling this page) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs

1238155 五、發明說明（3〇 ) e) 試劑和溶劑爲商業產物，且不純化便使用； f) 在氮下操作反應；和 g) 使用艾納特克（Analtech)單板矽膠板（250微米，Cat 第02521號）進行薄層層析（TLC)。實例只例1. (2反8,3及8)-2,3-乙氧基-3-苯丙醇（工）將後酸鈉（224克）和反式桂皮醇（2〇〇·〇克）與2公升二氯甲貌混合。經由燒瓶蒸氣空間持續緩慢氮掃動，並將混合物以冷水浴冷卻至15_20°C。以3小時期間添加過氧乙酸溶液（35%，381.2毫升），將溫度維持低於25r。過氧乙酸添加完成後，攪拌混合物2_3小時直到完成，如由HPLc 分析所示般。將混合物以冰浴冷卻至1〇°c，並以9 〇分鐘添加亞硫酸鈉（160克）於12〇〇毫升水中之溶液，保持溫度低於30°C。將相分離並以二氣甲烷（2〇〇毫升）萃取該水性相’以得到標題化合物之溶液。見例2. (2RS，3SR)-；3-(2-乙氧苯氧基經基一3_苯丙醇（Η) 將水（ 800毫升），氫氧化鈉（5〇%，83.1毫升），三丁基甲基氯化铵（75%，27.5毫升），和2-乙氧苯驗（306.72克）結合並在20-25°C攪拌。添加來自實例j之2,3_乙氧基苯丙醇的二氣甲统溶液，攪拌該二相混合物並加熱至4(rc内部溫度。在大氣壓以3 _ 4小時期間將二氣甲烷蒸餾。當二氯甲烷被移除後，内部溫度提高至60°C 2小時。無混合物冷卻至低於3 0 °C，添加甲苯（12〇〇毫升），攪摔混合物$分鐘。將相分離並以甲苯（8 〇〇毫升）萃取。結合甲苯溶液並 -33- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公爱） .II一——.-----________^____ (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 12381551238155 V. Description of the invention (3) e) Reagents and solvents are commercial products and used without purification; f) Operating the reaction under nitrogen; and g) Using Analtech veneer silicone plates (250 microns) , Cat No. 02521) for thin layer chromatography (TLC). Examples are only 1. (2 trans 8,3 and 8) -2,3-ethoxy-3-phenylpropanol (construction) Sodium post-sodium (224 g) and trans-cinnamyl alcohol (200. G) Mix with 2 liters of dichloroform. Continue a slow nitrogen sweep through the flask vapor space and cool the mixture to 15-20 ° C in a cold water bath. A solution of peracetic acid (35%, 381.2 ml) was added over a 3 hour period to maintain the temperature below 25r. After the addition of peroxyacetic acid was complete, the mixture was stirred for 2-3 hours until completion, as shown by HPLc analysis. The mixture was cooled to 10 ° C in an ice bath, and a solution of sodium sulfite (160 g) in 12,000 ml of water was added over 90 minutes, keeping the temperature below 30 ° C. The phases were separated and the aqueous phase 'was extracted with methane (200 ml) to give a solution of the title compound. See Example 2. (2RS, 3SR)-; 3- (2-ethoxyphenoxy group via 3-phenylpropanol (Η)) Water (800 ml), sodium hydroxide (50%, 83.1 ml) , Tributylmethylammonium chloride (75%, 27.5 ml), combined with 2-ethoxybenzene test (306.72 g) and stir at 20-25 ° C. Add 2,3_ethoxyphenylpropyl from Example j Alcohol digas solution, stir the biphasic mixture and heat to 4 ° C internal temperature. Dichloromethane is distilled at atmospheric pressure over a period of 3-4 hours. When the dichloromethane is removed, the internal temperature is increased to 60 ° C for 2 hours. Cool the mixture to below 30 ° C, add toluene (1200 mL), stir the mixture for $ minutes. Separate the phases and extract with toluene (8000 mL). Combine the toluene solution and- 33- The size of this paper applies to China National Standard (CNS) A4 (210 X 297 public love). II -------------________ ^ ____ (Please read the notes on the back before filling this page) Ministry of Economy Printed by the Intellectual Property Bureau Employee Consumer Cooperative 1238155

五、發明說明（31 經濟部智慧財產局員工消費合作社印製 2 5 C以1 N NaOH ( 2 x 400毫升）並以水（400毫升）清洗。在邵分眞空下維持内部溫度爲4〇_5(rc將曱苯溶液濃鈿。將殘餘油溶於甲基三級丁基醚（76〇毫升），以氟化鉀檢測將水含量改變爲低於0.1%。以標題化合物之晶體在 20-25 C將落液植晶，攪拌i小時，冷卻至2小時。將產生之固體過濾，以甲基三級丁基醚（2χ 2〇〇毫升，冷卻至_ 丄5 C )清洗’眞2下乾燥以產生256 1克標題化合物來自桂皮醇）。貝例3· (2RS，3SR)-3-(2_乙氧苯氧基）·2_羥基_3_苯基(三甲矽氧烷基）丙烷（ΠΙ) 知來自實例2之3-(2-乙氧苯氧基）_2_羥基-3-苯丙醇（1.44 克，5晕莫耳）和三乙胺（〇 77毫升，5 5毫莫耳）溶於乙酸乙酯（15毫升）中並冷卻至-17τ。以分鐘添加溶於5毫升乙酸乙醋之三甲基氯化矽烷（〇 64毫升，5 〇毫莫耳）並保持溫度低於-15Ό。此添加期間形成白色沉澱。低於-15 C攪:拌混合物1 5分鐘，添加2 〇毫升戊烷。以過濾移除固 a豆並在具全下濃縮濾液成爲一種混濁油。於秒石（μ 〇〇網目）上以4:1庚烷_乙酸乙酯溶析將油層析。將含產物之餘份濃縮產生1.80克（88.5%)清澈無色油狀標題化合物， H NMR (400.13 MHZ，CDC13) d 0.09 (s，9H)，1·47 (t，J=6.8 Hz，3H)，2.82 (d，J=5.2, 1H)，3.80 (m，3H)，4.0-4.11 (m，4H)， 5.08 (d, J=6.0? 1H)? 6.76 (m? 2H), 6.85 (m, 2H)? 7.2-7.45 (m, 5H); 13C NMR (100.62 MHZ，CDC13) d 0·0, 15.54, 63.34, 65.06, 75.22，83.71，114.28，118.60，121.51，122.95，127.84, -34- 本紙張尺度適用中國國家標準（CNS)A4規格（210 x 297公髮) -------1—-----—訂--------- (請先閱讀背面之注意事項再填寫本頁) 1238155 A7 B7 五、發明說明（32) =8.49, 128.84, 138.93, 148.34, 150.40; MS (ei) m/e 360 ; 只例4. (2RS，3SR)-3-(2•氧氧苯氧基）·2-甲磺醯氧基冬苯基-1-(三甲矽氧烷基）丙烷（IV) 將來自見例2之3-(2-乙氧苯氧基）-2-輕基-3-苯丙醇（1.44 克，5毫莫耳）和三乙胺（〇 77毫升，5 5毫莫耳）溶於乙酸乙酯（1 5毫升）中並冷卻至-17。〇。以丨〇分鐘添加溶於乙酸乙酯（5毫升）之三甲基氯化矽烷（〇64毫升，5.〇毫莫耳）並保持溫度低於_ 15 °c。此添加期間形成白色沉殿。低於_工5 C#見拌/昆合物15分鐘，添加三乙胺（〇·8亳升，57毫莫耳）’繼之溶於5毫升乙酸乙酯之甲烷氯化磺醯（〇46毫升’ 0.0毫莫耳），將溫度保持低於-^它。於低於—^它撥拌混合物1 5分鐘。添加戊烷（2〇毫升）並以過濾移除固體。將濾液在真空下濃縮濾液成為一種混濁油。於矽石 (23 0-400網目）上以4:1庚烷-乙酸乙酯溶析將油層析。將含產物之餾份濃縮產生2.00克（91.2%)單靜置時便固化之油狀標題化合物；熔點80-82.5 °C ; 4 NMR (400.13 MHZ， CDC13) d 0.17 (s，9H), 1.50 (t，J=6.8 Hz，3H)，3.06 (s5 3H)， 3.77 (dd，J=ll，6, 1H)，4·00 (dd，J=ll，6, 1H)，4.10 (q，J=6.8, 經濟部智慧財產局員工消費合作社印製 (請先閱讀背面之注意事項再填寫本頁) 2H)，5.07 (m，1H)，5.51 (d，J=4.4，1H)，6.75 (m，2H)，6.91 (m， 2H)，7·2-7·49 (m，5H); 13C NMR (100.62 MHZ，CDC13) d 0.0, 15.66，38.87，61.57，64.88，79.90，85.20，113.97，116.99, 121.32, 122.79，128,26，129.09，129.14，136.75，147.72, 149.95; MS (ei) m/e 438。實例5. (2RS，3SR)-3_(2-乙氧苯氧基）-2-甲磺醯氧基苯基 -35- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 1238155V. Description of the Invention (31 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 2 5 C was washed with 1 N NaOH (2 x 400 ml) and washed with water (400 ml). The internal temperature was maintained at 40 ° C under Shao Fenqiu 5 (rc) The toluene solution was concentrated. The residual oil was dissolved in methyl tert-butyl ether (760 ml), and the water content was changed to less than 0.1% by potassium fluoride detection. The crystals of the title compound were at 20 The falling liquid was seeded at -25 C, stirred for 1 hour, and cooled to 2 hours. The resulting solid was filtered, and washed with methyltributyl ether (2 × 200 ml, cooled to _ 丄 5 C) and washed '眞 2 And dried to yield 256 1 g of the title compound from Cinyl alcohol). Example 3 · (2RS, 3SR) -3- (2_ethoxyphenoxy) · 2_hydroxy_3_phenyl (trimethoxysilyl) ) Propane (III) Known from Example 2 3- (2-ethoxyphenoxy) -2-hydroxy-3-phenylpropanol (1.44 g, 5 hamol) and triethylamine (07 77 ml, 5 5 MM) was dissolved in ethyl acetate (15 mL) and cooled to -17τ. Trimethylsilyl chloride (0 64 mL, 50 mM) dissolved in 5 mL of ethyl acetate was added in minutes and kept temperature Below -15 ° C. A white precipitate is formed during this addition. Stir below -15 C: stir the mixture for 15 minutes, add 20 ml of pentane. Filter to remove solid beans and concentrate the filtrate to a turbid oil. The oil was chromatographed on spar (μμ mesh) with 4: 1 heptane-ethyl acetate. The remainder of the product was concentrated to give 1.80 g (88.5%) of the title compound as a clear, colorless oil, H NMR (400.13 MHZ, CDC13) d 0.09 (s, 9H), 1.47 (t, J = 6.8 Hz, 3H), 2.82 (d, J = 5.2, 1H), 3.80 (m, 3H), 4.0-4.11 (m, 4H), 5.08 (d, J = 6.0? 1H)? 6.76 (m? 2H), 6.85 (m, 2H)? 7.2-7.45 (m, 5H); 13C NMR (100.62 MHZ, CDC13) d 0 · 0, 15.54, 63.34, 65.06, 75.22, 83.71, 114.28, 118.60, 121.51, 122.95, 127.84, -34- This paper size applies to China National Standard (CNS) A4 specifications (210 x 297) ----- --1 —-----— Order --------- (Please read the notes on the back before filling out this page) 1238155 A7 B7 V. Description of the invention (32) = 8.49, 128.84, 138.93, 148.34, 150.40; MS (ei) m / e 360; only example 4. (2RS, 3SR) -3- (2 • oxyoxyphenoxy) · 2-methanesulfonyloxy Phenyl-1- (trimethoxysilyl) propane (IV) will be from 3- (2-ethoxyphenoxy) -2-lightyl-3-phenylpropanol (1.44 g, 5 mmol) from Example 2 Mol) and triethylamine (077 ml, 55 mmol) were dissolved in ethyl acetate (15 ml) and cooled to -17. 〇. Trimethylsilyl chloride (0 64 ml, 5.0 mmol) dissolved in ethyl acetate (5 ml) was added over 10 minutes and the temperature was kept below -15 ° C. A white sanctum is formed during this addition. Below _ 工 5 C # see Mix / Kun compound for 15 minutes, add triethylamine (0.8 liters, 57 mmol), followed by 5 ml of ethyl acetate in methanesulfonium chloride (〇46 Ml '0.0 millimolar), keep the temperature below-^ it. Below-^ it stirs the mixture for 15 minutes. Pentane (20 ml) was added and the solids were removed by filtration. The filtrate was concentrated under vacuum to a cloudy oil. The oil was chromatographed on silica (23 0-400 mesh) with 4: 1 heptane-ethyl acetate. The product-containing fractions were concentrated to give 2.00 g (91.2%) of the title compound as an oil that solidified upon standing alone; melting point 80-82.5 ° C; 4 NMR (400.13 MHZ, CDC13) d 0.17 (s, 9H), 1.50 (t, J = 6.8 Hz, 3H), 3.06 (s5 3H), 3.77 (dd, J = ll, 6, 1H), 4.00 (dd, J = ll, 6, 1H), 4.10 (q, J = 6.8, printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs (please read the notes on the back before filling this page) 2H), 5.07 (m, 1H), 5.51 (d, J = 4.4, 1H), 6.75 (m , 2H), 6.91 (m, 2H), 7.2-7.49 (m, 5H); 13C NMR (100.62 MHZ, CDC13) d 0.0, 15.66, 38.87, 61.57, 64.88, 79.90, 85.20, 113.97, 116.99 , 121.32, 122.79, 128,26, 129.09, 129.14, 136.75, 147.72, 149.95; MS (ei) m / e 438. Example 5. (2RS, 3SR) -3_ (2-ethoxyphenoxy) -2-methanesulfonyloxyphenyl-35- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) ) 1238155

五、發明說明（於） -1-丙醇（V) (請先閱讀背面之注意事項再填寫本頁) 知來自實例2之3-(2-乙氧苯氧）-2-羥基苯丙醇（〇 288 克，1¾莫耳）和三乙胺（0·15毫升，1;1毫莫耳）溶於乙酸經濟部智慧財產局員工消費合作社印製酉曰（5亳升）中並冷卻至-17t。以1〇分鐘添加溶於乙酸乙酉旨（2毫升）之三甲基氯化矽烷（〇13毫升，ι 〇毫莫耳）並保持溫度低於_15χ：。此添加期間形成白色沉澱。低於 C擾拌混合物1 5分鐘，添加三乙胺（015毫升，1丨毫莫耳）’繼之溶於乙酸乙@旨（2毫升）之甲垸氯化續醯（〇〇85毫升，1·1亳莫耳），將溫度保持低於-15。〇。於低於_15。〇擾拌混合物15分鐘。添加氫氯酸（2N，2毫升）並任由混合物回溫至20-25X：並攪拌3 0分鐘。將相分離並以飽和水性氯化鈉溶液（5毫升）清洗有機相並在硫酸鈉上乾燥。將溶液蒸發以產生0.377克油。於石夕石（230_400網目）上以4 : 1 庚規·乙酸乙酯溶析將油層析。將含產物之餾份濃縮產生〇 · 3 3克（9 1 % )當靜置時便固化之油狀標題化合物；11^83-86〇C; NMR (400.13 MHZ? CDC13) d 1.66 (t3 J=8.2 Hz, 3H)9 2.85 (s，3H)，4.14-4.35 (m，4H)，5.12 (m，1H)，5.52 (d, J=6.1 Hz), 6.8-7.15 (m? 4H), 7.5-7.7 (m, 5H); 13C NMR (100.62 MHZ，CDC13) d 14.73，37.80，62.19，64.27，81.40，84.04, 112.88，117.19，120.67，122.86，127.40，128.77，128.86, 137.02, 146.40, 149.30; MS (ei) m/e 366。實例6· (2RS，3RS)-1，2-乙氧基-3-(2·乙氧苯氧基）-3-苯基丙烷（VI) 將來自實例2之3-(2-乙氧苯氧基）-2-羥基-3-苯基-1-苯丙 -36- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公爱） 1238155V. Description of the invention (Yu) -1-propanol (V) (Please read the notes on the back before filling this page) Know that 3- (2-ethoxyphenoxy) -2-hydroxyphenylpropanol from Example 2 (〇288 g, 1¾ mol) and triethylamine (0.15 ml, 1; 1 mmol) were dissolved in the 酉 (5 亳 liter) printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs and cooled down to -17t. Trimethylsilyl chloride (0.13 ml, ιmmol) was dissolved in ethyl acetate (2 ml) over 10 minutes and the temperature was kept below -15x :. A white precipitate formed during this addition. Stir the mixture for 15 minutes below C, add triethylamine (015 ml, 1 mmol), followed by dissolution in ethyl acetate (2 ml) of formazan chloride (0.085 ml, (1.1 mol), keep the temperature below -15. 〇. Less than _15. 〇 Stir the mixture for 15 minutes. Add hydrochloric acid (2N, 2 mL) and allow the mixture to warm to 20-25X: and stir for 30 minutes. The phases were separated and the organic phase was washed with a saturated aqueous sodium chloride solution (5 ml) and dried over sodium sulfate. The solution was evaporated to give 0.377 g of oil. The oil was chromatographed on Shi Xishi (230_400 mesh) with 4: 1 heptanol · ethyl acetate. The product-containing fractions were concentrated to give 0.33 g (91%) of the title compound as an oil that solidified when left standing; 11 ^ 83-86 ° C; NMR (400.13 MHZ? CDC13) d 1.66 (t3 J = 8.2 Hz, 3H) 9 2.85 (s, 3H), 4.14-4.35 (m, 4H), 5.12 (m, 1H), 5.52 (d, J = 6.1 Hz), 6.8-7.15 (m? 4H), 7.5 -7.7 (m, 5H); 13C NMR (100.62 MHZ, CDC13) d 14.73, 37.80, 62.19, 64.27, 81.40, 84.04, 112.88, 117.19, 120.67, 122.86, 127.40, 128.77, 128.86, 137.02, 146.40, 149.30; MS (ei) m / e 366. Example 6 · (2RS, 3RS) -1,2-ethoxy-3- (2 · ethoxyphenoxy) -3-phenylpropane (VI) 3- (2-ethoxybenzene) from Example 2 (Oxy) -2-hydroxy-3-phenyl-1-phenylpropane-36- This paper size applies to China National Standard (CNS) A4 (210 X 297 public love) 1238155

五、發明說明（34 經濟部智慧財產局員工消費合作社印製醇（28.8克）和三乙胺（16·7毫升）溶於乙酸乙酯（i7〇毫升）中並冷卻至_20至-15。(：。添加溶於乙酸乙酯毫升）/三甲基氯化矽烷（13·2毫升）溶液並保持溫度具於_2〇和-15。〇 t間。添加完成後，將混合物在_2〇至_15χ：之間攪拌5分鐘0 於溶液添加甲烷氯磺醯（9·3亳升）並將溫度保持_2〇和_15 °c之間。添加三乙胺（16·7毫升），再次保持溫度於-和 •15°C之間。完成添加三乙胺後將混合物攪摔15分鐘。於反應混合物添加濃氫氣酸（8·3毫升）和水（92毫升）之溶液。任由混合物回溫至15_20。(：並攪拌45分鐘。&TLc 監控反應。將相分離並以碳酸氫鈉（5克）於45毫升水中之溶液，然後以12.5克氯化鈉和37.5毫升水之溶液清洗有機相。將有機相在眞空下濃縮爲一種油。添加甲苯（2〇〇毫升）並將溶液濃縮爲一種油，將其再溶於2〇〇毫升甲苯中。於甲苯溶液添加氫氧化鈉溶液（5〇%，3 6克），水（6 〇毫升）’和三丁基氯化甲銨（70%，2.5克）。以氮將混合物滌氣，在20-25°C高速攪拌約4 5分鐘，並以HPLC分析。今相分離並將該油性黃色界面保持與有機相在一起。以甲苯 (5 0毫升）萃取水性相並結合甲苯溶液。以飽和氯化鋼溶液（50毫升，12.5克NaCl和37.5毫升水）清洗甲苯溶液。將甲苯溶液在眞空下濃縮至6 0毫升降浴溫40°C )。添加甲醇 (:)00¾升）並將溶液濃縮爲體積60¾升。添加甲醇毫升）並再次將混合物濃縮爲體積6 0毫升，以得到標題化合物之溶液。 -37- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） ---.----1-------------訂--------- 請先閱讀背面之注意事項再填寫本頁} 1238155V. Description of the invention (34 The printed alcohol (28.8 g) and triethylamine (16.7 ml) of the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs are dissolved in ethyl acetate (i7 ml) and cooled to _20 to -15 (:. Add dissolved in ethyl acetate ml) / trimethylsilyl chloride (13. 2 ml) solution and keep the temperature between -20 and -15. T. After the addition is complete, the mixture is at _ 20 to _15χ: Stir between 5 minutes 0 Add methane chlorosulfonium sulfonium (9.3 liters) to the solution and keep the temperature between -20 and -15 ° c. Add triethylamine (16.7 ml ), Keep the temperature between-and • 15 ° C again. After adding triethylamine, stir the mixture for 15 minutes. Add a solution of concentrated hydrogen acid (8.3 ml) and water (92 ml) to the reaction mixture. Allow the mixture to warm to 15-20. (: And stir for 45 minutes. &TL; Monitor the reaction. The phases are separated and a solution of sodium bicarbonate (5 g) in 45 ml of water, then 12.5 g of sodium chloride and 37.5 ml The organic phase was washed with a solution of water. The organic phase was concentrated under air to an oil. Toluene (200 ml) was added and the solution was It was concentrated to an oil and redissolved in 200 ml of toluene. To the toluene solution was added a sodium hydroxide solution (50%, 36 g), water (60 ml) and tributylmethylammonium chloride. (70%, 2.5 g). The mixture was purged with nitrogen, stirred at high speed at 20-25 ° C for about 4 5 minutes, and analyzed by HPLC. This phase was separated and the oily yellow interface was kept with the organic phase. The toluene (50 ml) was used to extract the aqueous phase and combined with the toluene solution. The toluene solution was washed with a saturated steel chloride solution (50 ml, 12.5 g of NaCl and 37.5 ml of water). The toluene solution was concentrated to 60 ml under reduced pressure to reduce the bath temperature. 40 ° C). Methanol (: 00¾ liters) was added and the solution was concentrated to a volume of 60¾ liters. Methanol was added) and the mixture was again concentrated to a volume of 60 ml to obtain a solution of the title compound. -37- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) ---.---- 1 ------------- Order ----- ---- Please read the notes on the back before filling out this page} 1238155

經濟部智慧財產局員工消費合作社印製五、發明說明細）實例7· (2RS，3RS)-3-(2-乙氧苯氧基）_2-羥基-3_苯基丙胺 (VII) 於實例6之甲醇溶液添加270亳升甲醇和3〇〇毫升氫氧化按。於密封容器中攪摔該混合物並加熱至4〇Ό3小時。3 小時後，將反應物冷卻並以HPLC分析。添加二氯甲烷 (223亳升）並攪掉混合物然後任由沉降。將相分離並以二氯甲烷（2 X 100毫升）萃取。結合有機相並在眞空下蒸餾成爲體積爲300毫升。將二氣甲烷（18〇毫升）加回溶液。以 250耄升清洗二氯甲垸溶液。以1〇〇毫升二氯甲燒萃取水並結合二氯甲烷。於結合之二氯甲燒溶液添加250毫升水和1 〇亳升濃氫氯酸之溶液。以添加更多HC1碉整p Η至低於2。禮拌混合物然後任由沉降。將相分離並以250毫升水萃取。結合水性相並以46毫升二氯甲烷清洗。於水性相添加二氯甲燒（144毫升）並以5〇%水性NaOH (約10克）調整pH至大於12。將相分離並以72毫升二氯曱烷萃取。結合有機相並蒸餾至體積爲2〇〇毫升。添加異丙醇（200毫升）並將混合物蒸餾至體積爲2〇〇毫升。添加異丙醇（2 0 0毫升）並將溶液再次蒸餾至體積爲2〇〇毫升。添加甲烷磺酸（7.9克）並在20-25°C攪摔混合物2小時。將產生之漿液冷卻至0-5 C並檟:拌6 0分鐘。將固體過遽並以 100毫升異丙醇清洗。將產生之固體在眞空爐中於⑼^乾燥，產生24.5克如甲烷磺酸鹽般之標題化合物（整體64% 來自3-(2•乙氧苯氧基-2-羥基-3-苯基-1-丙醇）。 -38- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公爱) ' "------ ----I---^--------I (請先閱讀背面之注意事項再填寫本頁) 1238155 經濟部智慧財產局員工消費合作社印製 A7 B7 五、發明說明（36 ) 實例8.(戰徽)-N-氯乙㈣·H2_乙氧笨氧_輕基-3-***（VIII) 攪拌（2RS，3RSH，2_乙氧基_3_(2_乙氧笨氧基）3苯丙燒 (47.7克）和碳酸甲酯（700毫升）形成白色 ^ ^ ^ _ κ吸。添加二乙胺（52¾升）並使用冰/Ha浴將混合物冷 1 王 6-10C。以 3 0分鐘期間添加氣乙醯氯（13.8毫升）/碳酸甲酯毫升）落液並保持溫度介於4-10Χ之間。攪拌混合物^】時。以 5〇〇毫升H2〇，然後以500毫升3%水性Naa落液清洗該混合物。在40X於眞空下濃縮有機層產生深色油。添加異丙醇（500毫升）並將混合物再次濃縮以移除任何殘餘之碳酸甲酯，產生標題化合物。 ' 實例9· (2RS，3RS)-2如_(2_乙氧苯氧基）苄基]嗎啉_5_酮 (IX) 以200毫升異丙醇攪拌來自實例8之產物形成漿液。製備異丙醇（ 305毫升）和三級丁氧化鉀（3〇·6克）之溶液。將此添加於該異丙醇漿液，並以冰浴將反應溫度維持介於2〇_ 23°C之間。在20-25°C攪拌該混合物！小時。以添加i Ν HC1 (約210¾升）將混合物之pjj調整至6·4。在眞空下蒸發混合物成爲油。將水（170毫升），甲苯（150毫升）添加於殘渣並將混合物攪拌5分鐘。以1 〇〇毫升曱苯萃取水性層。結合該甲苯萃取物並以100毫升IN HC1和100亳升1〇% NaCl溶液清洗。將曱苯溶液蒸發爲油並將殘渣再次溶於 240毫升甲苯，得到標題化合物之溶液。實例10· (2RS，3RS)-2_[ α _(2_乙氧苯氧基）芊基]嗎琳 -39- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -ϋ n n i n H ϋ n I» -ϋ n ϋ n ϋ ϋ n H ϋ 一一口、 n n n I n I I I (請先閱讀背面之注意事項再填寫本頁) 1238155 A7 ---- B7 五、發明說明（37 ) (Reboxetine ) 以187毫升曱苯稀釋vitride/甲苯（65%，187毫升）溶液並將S液冷卻至低於5 °C。以1小時添加來自實例9之甲苯溶液，並將溫度維持低於5 °C。完成添加後攪拌混合物1 5分鐘。添加6 0克50% NaOH於足量水中使成爲體積爲35〇毫升之落液，保持溫度低於55°C。添加完成後在55°C授摔該二相混合物。以5 %破酸鈉溶液（3 X 170毫升）清洗該甲苯相。於甲苯溶液添加水並添加IN HC1得到p Η爲3.11。以 4 8 0毫升甲苯萃取水性相。於水溶液添加甲苯（48〇毫升）並以50% NaOH將pH調整至高於1 2。以240毫升曱苯萃取該水性相。將二種甲苯溶液結合並以碳酸鈉溶液（5 %， 175毫升）和水（175毫升）清洗。將甲苯蒸發以產生32克無鹼般之標題化合物。實例11 · (2RS，3RS)-2-[ π -(2-乙氧苯氧基）爷基]嗎琳曱規續酸鹽將來自實例1 0之油溶於122毫升丙酮中，並在20-25°C與 2克活性碳（例如，Darco G-60，卡爾根碳公司（calgon Carbon Corporation);或 Norit，美國諾利特公司（American Norit Corporation)和2克寅式鹽一起禮掉i小時。將混合物過濾、並將滤液體積調整爲320毫升。將溶液冷卻至〇。〇並添加曱烷磺酸（5.1毫升）。在〇°C攪拌混合物7 0分鐘，然後過濾。以100毫升丙酮清洗該固體並在氮下乾燥，產生3〇〇8 克白色固體。將固體於200毫升丙酮中漿液化，並在5〇t 攪摔2小時。將漿液冷卻至〇°C 3 0分鐘並過濾。將固體在 -40- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） !!睿 (請先閱讀背面之注意事項再填寫本頁) 訂---- 經濟部智慧財產局員工消費合作社印製 1238155 A7 ----------B7 五、發明說明（38 ) 尸乾燥，產生27.72克標題化合物（整體來自3_(2_ 乙氧苯氧基）-2-羥基-3-苯基丙胺）。二將所有公告，.專利和專利文件併入本文供參考，即使獨立併入供參考。本發明頃參考各種特定且較佳之具體實二和技術敘述。然而，應該瞭解可以作許多變化和調整，一万面維持於本發明之精義和範圍内。正’ ---------—--------訂--------- (請先閱讀背面之注意事項再填寫本頁} 經濟部智慧財產局員工消費合作社印製Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 5. Details of the invention) Example 7 · (2RS, 3RS) -3- (2-ethoxyphenoxy) _2-hydroxy-3_phenylpropylamine (VII) 6 of methanol solution was added 270 liters of methanol and 300 ml of hydroxide. The mixture was stirred in a sealed container and heated to 40.3 hours. After 3 hours, the reaction was cooled and analyzed by HPLC. Dichloromethane (223 liters) was added and the mixture was stirred off and then allowed to settle. The phases were separated and extracted with dichloromethane (2 X 100 ml). The organic phases were combined and distilled under vacuum to a volume of 300 ml. Digas methane (180 ml) was added back to the solution. Wash the dichloromethane solution with 250 liters. Water was extracted with 100 ml of dichloromethane and combined with dichloromethane. To the combined dichloromethane solution was added a solution of 250 ml of water and 10 liters of concentrated hydrochloric acid. To add more HC1, adjust p to less than 2. The mixture is then allowed to settle. The phases were separated and extracted with 250 ml of water. The aqueous phases were combined and washed with 46 ml of dichloromethane. Dichloromethane (144 ml) was added to the aqueous phase and the pH was adjusted to greater than 12 with 50% aqueous NaOH (about 10 g). The phases were separated and extracted with 72 ml of dichloromethane. The organic phases were combined and distilled to a volume of 200 ml. Isopropanol (200 ml) was added and the mixture was distilled to a volume of 200 ml. Isopropanol (200 ml) was added and the solution was distilled again to a volume of 200 ml. Add methanesulfonic acid (7.9 g) and stir the mixture at 20-25 ° C for 2 hours. Cool the resulting slurry to 0-5 C and simmer: mix for 60 minutes. The solid was filtered and washed with 100 ml of isopropanol. The resulting solid was dried in an air oven at ^^, yielding 24.5 g of the title compound as a methanesulfonate (64% overall from 3- (2 • ethoxyphenoxy-2-hydroxy-3-phenyl- 1-propanol). -38- This paper size applies to China National Standard (CNS) A4 specification (210 X 297 public love) '" ------ ---- I --- ^ ---- ---- I (Please read the notes on the back before filling out this page) 1238155 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs A7 B7 V. Description of Invention (36) Example 8. (Battle of War) -N-chloroethyl ㈣ · H2_ethoxybenzyloxy_lightyl-3-amphetamine (VIII) stirred (2RS, 3RSH, 2_ethoxy_3_ (2_ethoxybenzyloxy) 3 phenylpropane (47.7 g) and carbonic acid Methyl ester (700 ml) formed a white ^^^ _ κ suction. Diethylamine (52¾ liters) was added and the mixture was cooled using an ice / Ha bath for 1 to 6-10C. Gas ethyl chloride (13.8) was added over 30 minutes. Ml) / methyl carbonate ml) The solution was dropped and kept at a temperature between 4-10 ×. The mixture was stirred. The mixture was washed with 500 ml of H2O, and then with 500 ml of 3% aqueous Naa. Concentrate the organic layer at 40X under vacuum to produce a dark oil. Isopropanol (500 ml) was added and the mixture was concentrated again to remove any residual methyl carbonate to give the title compound. 'Example 9 · (2RS, 3RS) -2 as _ (2_ethoxyphenoxy) benzyl Methyl] morpholine-5_one (IX) The product from Example 8 was stirred to form a slurry with 200 ml of isopropanol. A solution of isopropanol (305 ml) and tertiary potassium butoxide (30.6 g) was prepared. This was added to the isopropanol slurry, and the reaction temperature was maintained between 20-23 ° C in an ice bath. The mixture was stirred at 20-25 ° C! For hours. To add Ν HC1 (about 210¾ liters) ) Adjust the pjj of the mixture to 6.4. Evaporate the mixture into oil under vacuum. Add water (170 ml) and toluene (150 ml) to the residue and stir the mixture for 5 minutes. Extract water with 100 ml of toluene The toluene extract was combined and washed with 100 ml of IN HC1 and 100 ml of 10% NaCl solution. The toluene solution was evaporated to an oil and the residue was redissolved in 240 ml of toluene to give a solution of the title compound. Example 10 · (2RS, 3RS) -2_ [α _ (2_ethoxyphenoxy) fluorenyl] morphine-39- This paper is applicable to the standard National Standard (CNS) A4 Specification (210 X 297 mm) -ϋ nnin H ϋ n I »-ϋ n ϋ n ϋ ϋ n H ϋ one bite, nnn I n III (Please read the precautions on the back before (Fill in this page) 1238155 A7 ---- B7 V. Description of the invention (37) (Reboxetine) Dilute the vitride / toluene (65%, 187 ml) solution with 187 ml of toluene and cool the S liquid to below 5 ° C. The toluene solution from Example 9 was added over 1 hour and the temperature was maintained below 5 ° C. After the addition was complete, the mixture was stirred for 15 minutes. 60 g of 50% NaOH was added to a sufficient amount of water to make a liquid drop of 350 ml, keeping the temperature below 55 ° C. After the addition is complete, the two-phase mixture is shaken at 55 ° C. The toluene phase was washed with a 5% sodium decomposing solution (3 X 170 ml). Water was added to the toluene solution and IN HC1 was added to obtain p Η of 3.11. The aqueous phase was extracted with 480 ml of toluene. Toluene (48 ml) was added to the aqueous solution and the pH was adjusted to above 12 with 50% NaOH. The aqueous phase was extracted with 240 ml of toluene. The two toluene solutions were combined and washed with a sodium carbonate solution (5%, 175 ml) and water (175 ml). Toluene was evaporated to give 32 g of the title compound without alkali. Example 11 · (2RS, 3RS) -2- [π-(2-ethoxyphenoxy) yl] morpholinium salt The oil from Example 10 was dissolved in 122 ml of acetone at 20 -25 ° C with 2 grams of activated carbon (for example, Darco G-60, Calgon Carbon Corporation; or Norit, American Norit Corporation) and 2 grams of Yin salt i Hours. The mixture was filtered and the volume of the filtrate was adjusted to 320 ml. The solution was cooled to 0.0% and added with pinanesulfonic acid (5.1 ml). The mixture was stirred at 0 ° C. for 70 minutes and then filtered. The solid was washed and dried under nitrogen to yield 3.08 g of a white solid. The solid was slurried in 200 ml of acetone and stirred for 2 hours at 50 t. The slurry was cooled to 0 ° C for 30 minutes and filtered. .The solid is at -40- This paper size applies Chinese National Standard (CNS) A4 specification (210 X 297 mm) !! Rui (Please read the precautions on the back before filling this page) Printed by the Consumer Cooperative of the Property Bureau 1238155 A7 ---------- B7 V. Description of Invention (38) 27.72 g of the title compound (whole from 3_ (2_ethoxyphenoxy) -2-hydroxy-3-phenylpropylamine) II. All publications, patents and patent documents are incorporated herein by reference, even if they are individually incorporated by reference The present invention is described with reference to various specific and preferred embodiments and technical descriptions. However, it should be understood that many changes and adjustments can be made, and that 10,000 aspects are maintained within the spirit and scope of the present invention. Positive '------- ----------- Order --------- (Please read the notes on the back before filling out this page} Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs

1238155 A7 _B7 五、發明說明（39 )1238155 A7 _B7 V. Description of the invention (39)

圖IFigure I

— — — — — — — — — — — I I I I I I I j^>1 — — — ! — — — (請先閱讀背面之注意事項再填寫本頁)— — — — — — — — — — — — I I I I I I I j ^ > 1 — — —! — — (Please read the notes on the back before filling this page)

本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 1238155 A7 _B7 五、發明說明（4〇 )This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1238155 A7 _B7 V. Description of the invention (40)

本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 1238155 A7 B7 五、發明說明（41 )This paper size is applicable to China National Standard (CNS) A4 (210 X 297 mm) 1238155 A7 B7 V. Description of the invention (41)

圖IIIFigure III

VilaVila

(R)n €Τ(R) n € Τ

〇 ?「Ι r^/〇4J 丨子⑽ ⑻丨1- ·〇? 「Ι r ^ / 〇4J 丨子 ⑽ ⑻ 丨 1- ·

Sh ---------着 (請先閱讀背面之注意事項再填寫本頁) [Xa — — — — — — 經濟部智慧財產局員工消費合作社印製 4- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 1238155 Α7 Β7 五、發明說明（42By Sh --------- (Please read the notes on the back before filling this page) [Xa — — — — — — Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 4- This paper is applicable to Chinese countries Standard (CNS) A4 specification (210 X 297 mm) 1238155 Α7 Β7 V. Description of invention (42

圖IVFigure IV

c：V^〇H 0c: V ^ 〇H 0

OHOH

ill· —------i (請先閱讀背面之注意事項再填寫本頁)ill · —------ i (Please read the notes on the back before filling this page)

R- 0°.R- 0 °.

ί>ί >

Vb 訂·Vb Order ·

經濟部智慧財產局員工消費合作社印製 -45- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐）Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs -45- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm)

* - — n 修正年月Π久，、 η !補元 Α4 C4 翁|專利説明書 1238155 公說明書修正頁(90年1月）名稱中文英文*-— N correction year, month, year, η! Supplementary Α4 C4 Weng | Patent Specification 1238155 Official Specification Correction Page (January 1990) Name Chinese English

製備芳基醚之方法，用於其之中法 "i^^^^^PREPARING ARYL ETHERS THE -— AND FOR PREPARING 姓名國籍發明創作y 住、居所姓名 (名稱） 1·凱文E·海尼卡 2·^拉伊莉莎伯莫西尼 3·埶斯道格拉斯美斯托均美國 ^,國3西根州波塔吉市沙波林圓圜6136號 • ί國竺西根州卡林麻梅族市西尼克路5964號 3·吴國密西根州波塔吉市櫻桃景大道397號美商法瑪西亞-普強公司經濟部智慧財產局員工消費合作社印製申請人國籍住、居所 (事務所) 代表人姓名美國美國密西根州卡林麻梅族市漢瑞特街301號羅伯J.梅森海德Method for preparing aryl ether, used in the method " i ^^^^^ PREPARING ARYL ETHERS THE--AND FOR PREPARING Name Nationality Invention Invention y Name of residence, residence (name) 1. Kevin E. Heine Card 2 ^ La Eliza Bermosini 3. Ms. Douglas Mesto both United States ^, Country 3, No. 6136 Shapolin Circle, Potagi City, Siegen State • Carol Mami, Carin No. 5964, Sinike Road, Shenzhen 3.Wu Guojia, No. 397 Cherry View Avenue, Portage, Michigan Name Robert J. Mason Hyde, 301 Hanrett Street, Carlin Mami City, Michigan, USA

X 297 X釐）弟8^22940號專利申請案說明書修正頁(9〇年1月^X 297 X PCT) Patent Application No. 8 ^ 22940 Specification Revision Sheet (January 1990 ^

、發明説明（ ΐϋ：、本發明係關於製備某些用以作為抗抑鬱劑之芳基醚的改良^備方法。本發明亦關於該方法中有用之中間體，以及此類中間體之製備方法。 1980年1 0月2 1日核發之美國專利第4,229,449號表示化學式（A)之化合物2. Description of the invention (1): The present invention relates to an improved method for preparing certain aryl ethers used as antidepressants. The present invention also relates to intermediates useful in the method, and a method for preparing such intermediates US Patent No. 4,229,449 issued on October 21, 1980, represents a compound of formula (A)

㈧其中 η和nl獨立為1，2或3 ; R和Ri基可以相同或相異，各為氫；自素；卣素烷基；麟；氧基；視需要取代之Ci'垸基；視需要又芳基-CVC6烷基；視需要取代之芳基_ _ 經濟部中央標準局員工消費合作社印製 --J__ U----tII (請先閱讀背面之注意事項再填寫本頁) N02 ; NR5R6，其中1和R6獨立為氫或烷基，或i者二個鄰近R基或二個鄰近Rl基一起形成一種七反應基； ’ h為氫；視需要取代之Cl-Cl2烷基，或芳基π”。烷基； &和R4基可以相同或相異，各為氫，视需要取代6之" 烷基，cvc：4烯基，cvc：4炔基，視需要取代之芳芙c / -4-㈧ where η and nl are independently 1, 2 or 3; R and Ri groups may be the same or different and each is hydrogen; autogen; fluorene alkyl; lin; oxy; optionally substituted Ci 'fluorene; Need aryl-CVC6 alkyl group; aryl group substituted if necessary _ _ Printed by Employee Consumer Cooperative of Central Bureau of Standards, Ministry of Economic Affairs-J__ U ---- tII (Please read the precautions on the back before filling this page) N02 NR5R6, wherein 1 and R6 are independently hydrogen or alkyl, or two adjacent R groups or two adjacent R1 groups together form a seven-reaction group; 'h is hydrogen; Cl-Cl2 alkyl substituted as required, Or aryl π ". Alkyl; & and R4 groups may be the same or different, each being hydrogen, and optionally substituted for " alkyl, cvc: 4 alkenyl, cvc: 4 alkynyl, substituted as necessary Fanfu c / -4-

V V 12381説122940號專利申請案說明書修正頁(90年1月）五、發明説明（2 ) L_------------ 烷基：視需要取代之q—C7環烷基，或1和1輿其鍵結之氮原子形成-種是需要取代之五原子或六原子飽^或;飽和之雜單環反應基，其視需要包含其它屬於〇，雜原子；或反2和R4 一起形成-CH2-CH2-反應基；或一種其製藥可接受之鹽類。所揭示之化合物擁有抗抑鬱劑活性。尤其’美國專利第4,229,449號揭示該化合物： 2-[α-(2-乙氧苯氧基）芊基]嗎啉： (請先閲讀背面之注意事項再填寫本頁) .瞀· 〇&VV 12381 said the amendment page of the specification of Patent Application No. 122940 (January 1990) V. Description of the invention (2) L _------------ Alkyl: q-C7 cycloalkyl substituted as required Or 1 and 1 form a bonded nitrogen atom-a kind of 5 or 6 atoms which need to be substituted ^ or; saturated heteromonocyclic reactive group, which contains other heteroatoms belonging to 0, if necessary; or trans 2 Forms a -CH2-CH2- reactive group with R4; or a pharmaceutically acceptable salt thereof. The disclosed compounds possess antidepressant activity. In particular, US Patent No. 4,229,449 discloses this compound: 2- [α- (2-ethoxyphenoxy) fluorenyl] morpholine: (Please read the precautions on the back before filling this page). 本页 · 〇 &

•、11 經濟部中央標準局員工消費合作社印製和其製藥可接受之鹽類，其擁有有用之抗抑鬱劑性質此化合物亦已知為Reb〇xetine。如在圖1 V中所說明般，美國專利第5,068,433號（1991 1 1月26日核發）和相關之美國專利第5,391，735號（1995」月21日核發）揭示用以製備化學式v][b化合物單一非鐘異構物之方法和中間體：•, 11 Printed by the Consumer Standards Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs and its pharmaceutically acceptable salts with useful antidepressant properties. This compound is also known as Reboxetine. As illustrated in Figure 1V, U.S. Patent No. 5,068,433 (issued on January 26, 1991) and related U.S. Patent No. 5,391,735 (issued on January 21, 1995) disclose the preparation of chemical formula v] [ Method and intermediate of single non-bell isomer of compound b:

(VIb) 本紙張尺度適财g s(VIb) The paper size is suitable for g s

Claims

123為萏22940號專利申請案中文申請專利範圍替換本(92年10月) 8 8 8 8 A B c D 9Ζΐϋ. 〇β 公本申請專利範圍一種製備式Vila之芳基醚之方法：123 is the patent application No.22940. Chinese patent application scope replacement (October 1992) 8 8 8 8 A B c D 9Zΐϋ. 〇β public patent application scope A method for preparing aryl ether of formula Vila:

(^l)ni Vila 其中 η和nl獨立為1，2或3 ; 尺和心基可以相同或相異，各為氫或（^-(：6烷氧基；其包括： a) 將取代或未取代之反式桂皮醇氧化，得到式I a 之中間體環氧化物： ,0 OH(^ l) ni Vila wherein η and nl are independently 1, 2, or 3; the ruler and the heart group may be the same or different, each is hydrogen or (^-(: 6 alkoxy; which includes: a) will replace or Oxidation of unsubstituted trans-cinnitol to give intermediate epoxides of formula Ia:, 0 OH

(Ι^ι)ηΓ la b) 將該環氧化物與取代或未取代之苯酚反應，得到式Ila之二醇：(Ι ^ ι) ηΓ la b) reacting the epoxide with a substituted or unsubstituted phenol to obtain a diol of formula Ila:

(^ι)ηΐ c)將該二醇與矽烷化試劑反應，得到式Ilia之醇： O:\61\61888-921006.DOC5 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 8 8 8 8 ABCD 1238155 申請專利範圍(^ ι) ηΐ c) The diol is reacted with a silylating agent to obtain an alcohol of the formula Ilia: O: \ 61 \ 61888-921006.DOC5 This paper size is applicable to China National Standard (CNS) A4 (210 X 297) (%) 8 8 8 8 ABCD 1238155 Patent Application Scope

其中P為一種矽烷基鍵聯反應基；得到 d)將式Ilia之醇與磺酸之反應性衍生物反應式IVa之化合物：Where P is a silane-based reactive group; d) reacting an alcohol of formula Ilia with a reactive derivative of a sulfonic acid; a compound of formula IVa:

IVa 其中Ra為磺酸之殘基； e)將P從式IVa之化合物移除，得到式Va之醇IVa where Ra is a residue of a sulfonic acid; e) removing P from a compound of formula IVa to obtain an alcohol of formula Va

(^ι)ηι Va f)將磺醯氧基取代，得到式VI a之環氧化物 (R)n 4> Via O:\61\61888-921006.DOC5 本紙張尺度適用中國國家標準(CNS) A4規格(210χ 297公釐) 1238155 έβ8 C8 D8 六、申請專利範圍和 g) 將該環氧化物與氨反應，得到式Vila之化合物。 2.根據申請專利範圍第1項之方法，其更包括： h) 將式Vila之化合物(^ ι) ηι Va f) Substitute sulfonyloxy group to obtain epoxide (R) n 4 of formula VI a > Via O: \ 61 \ 61888-921006.DOC5 This paper size applies Chinese National Standard (CNS) A4 specification (210 x 297 mm) 1238155 β β8 C8 D8 6. Application scope and g) The epoxide is reacted with ammonia to obtain the compound of formula Vila. 2. The method according to item 1 of the patent application scope, further comprising: h) adding a compound of formula Vila

Vila 其中 η和nl獨立為1，2或3 ; 尺和心基可以相同或相異，各為氫或(^-^烷氧基；與式HOOCCH2L之羧酸或其反應性衍生物反應，其中L 為離去基，得到製備Villa之醯胺：Vila wherein η and nl are independently 1, 2 or 3; the ruler and the heart group may be the same or different, each being hydrogen or (^-^ alkoxy; reacting with a carboxylic acid of the formula HOOCCH2L or a reactive derivative thereof, wherein L is a leaving group to obtain amidine for the preparation of Villa:

i)將式Villa之化合物反應，得到式IXa之化合物反 O:\61\61888-921006.DOC5 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 8 8 8 8 A B c Di) The compound of the formula Villa is reacted to obtain the compound of the formula IXa: O: \ 61 \ 61888-921006.DOC5 This paper size applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 8 8 8 8 AB c D

1238155 申請專利範圍應： ζτ IXa 且 j )將式IXa之化合物還原，得到以下式之對應化合物： (R)n- 3. 根據申請專利範圍第2項之方法，其更包括形成一種嗎琳化合物之1醫藥可接受的鹽類。 4. 根據申請專_利範圍第1項之方法，其係製備式VII之化合物：1238155 The scope of the patent application should be: ζτ IXa and j) The compound of formula IXa is reduced to obtain the corresponding compound of the following formula: (R) n- 3. According to the method of item 2 of the scope of patent application, which further includes the formation of a morphine compound 1 pharmaceutically acceptable salt. 4. The method according to item 1 of the patent application scope, which is to prepare the compound of formula VII:

其包括： O:\61\61888-921006.DOC5 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐)It includes: O: \ 61 \ 61888-921006.DOC5 This paper size is applicable to China National Standard (CNS) A4 (210X 297 mm)

8 8 8 8 A B c D 1238155 六、申請專利範圍 a)將取代或未取代之反式桂皮醇氧化，得到式I之中間體環氧化物：8 8 8 8 A B c D 1238155 6. Scope of patent application a) Oxidation of substituted or unsubstituted trans-cinnamyl alcohol to obtain intermediate epoxide of formula I:

b)將該環氧化物與取代或未取代之苯酚反應，得到式11之二醇：b) reacting the epoxide with a substituted or unsubstituted phenol to obtain a diol of formula 11:

c)將該二醇與矽烷化試劑反應，得到式III之醇：c) reacting the diol with a silylating agent to obtain an alcohol of formula III:

d)將式III之醇與磺酸之反應性衍生物反應，得到式IV之化合物：d) reacting an alcohol of formula III with a reactive derivative of a sulfonic acid to obtain a compound of formula IV:

O:\61\61888-921006.DOC5 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) A B c D 1238155 六、申請專利範圍 e )將三甲矽烷基從式I V之化合物移除，得到式V 之醇：O: \ 61 \ 61888-921006.DOC5 This paper size is applicable to Chinese National Standard (CNS) A4 (210 X 297 mm) AB c D 1238155 VI. Application scope of patent e) Move trimethylsilyl from compound of formula IV Divide to get the alcohol of formula V:

f)將磺氧基取代，得到式VI之環氧化物：f) Substitution of sulfoxy groups to give epoxides of formula VI:

且 g)將該環氧化物與氨反應，得到式V Π之化合物。 5. 根據申請專利範圍第4項之方法，其更包括製備式VII之化合物的甲烷磺酸鹽。 6. 根據申請專利範圍第4項之方法，其更包括： h)將式VII之化合物與氯乙醯氯反應，得到式VIII 之醯胺：、And g) reacting the epoxide with ammonia to obtain a compound of formula VII. 5. The method according to item 4 of the scope of patent application, which further comprises preparing a methanesulfonate of a compound of formula VII. 6. The method according to item 4 of the patent application scope, further comprising: h) reacting a compound of formula VII with chloroacetamidine to obtain amidine of formula VIII:

本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 8 8 8 8 A B c D 1238155 六、申請專利範圍 i)將式VIII之化合物反應，得到式IX之化合物： 0SThis paper size applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 8 8 8 8 A B c D 1238155 6. Application scope i) The compound of formula VIII is reacted to obtain the compound of formula IX: 0S

IXIX

〇且 j)將式I X之化合物還原，得到下式之對應嗎啉化合物：〇 and j) reducing the compound of formula I X to obtain the corresponding morpholine compound of the formula:

7.根據申請專利範圍第5項之方法，其更包括： h )將式VII之化合物與氯乙醯氯反應，得到式VIII 之醯胺：7. The method according to item 5 of the patent application scope, further comprising: h) reacting a compound of formula VII with chloroacetamidine to obtain amidine of formula VIII:

O:\61\61888-921006.DOC 5 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐) 1238155 、申請專利範圍 8 8 8 8 A BCD υ將式VIII之化合物反應，得到式ιχ2化合物 ORO: \ 61 \ 61888-921006.DOC 5 This paper size is applicable to Chinese National Standard (CNS) A4 specification (210X297 mm) 1238155, patent application range 8 8 8 8 A BCD υ The compound of formula VIII is reacted to obtain formula ιχ2 Compound OR

且化合：將製備IX之化合物還原’得到下式之舞應嗎琳And compounding: reducing the compound of preparation IX ’to obtain Mai Ying Lin

8·根據申請專利範圍第6或7項之方法，其包括形成合物之醫藥可接受的鹽類。馬p祙化 9.根據申請專利範圍第8項之方法，其中該鹽# 酸鹽。 ^甲埝， 10· —種製備式I a環氧化物之方法： (Ri)nl8. A method according to item 6 or 7 of the scope of patent application, which comprises forming a pharmaceutically acceptable salt of a compound.马化祙化 9. The method according to item 8 of the scope of patent application, wherein the salt is an acid salt. ^ Formamidine, 10 · —A method for preparing epoxide of formula I a: (Ri) nl

la -8 a\6i\61888-921006.DOC 5 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐) 1238155 A8 B8 C8 D8 六、申請專利範圍其中R 1及η 1如申請專利範圍第1項所定義，其包括以過氧乙酸將對應之晞氧化la -8 a \ 6i \ 61888-921006.DOC 5 This paper size applies to Chinese National Standard (CNS) A4 specification (210X297 mm) 1238155 A8 B8 C8 D8 VI. Patent application scope, of which R 1 and η 1 are as in the patent application scope As defined in item 1, which includes oxidation of the corresponding tritium with peracetic acid

其中R i及11 1如申請專利範圍第1項所定義。 11. 一種製備式Ilia化合物之方法：Among them, R i and 11 1 are as defined in item 1 of the scope of patent application. 11. A method for preparing a compound of formula Ilia:

其中 η和nl獨立為1，2或3 ; 尺和！^基可_以相同或相異，各為氫或CrQ烷氧基；且 P為矽烷基键聯之反應基；其包括將式Ila之二醇：Where η and nl are independently 1, 2, or 3; ^ Groups may be the same or different, each being hydrogen or a CrQ alkoxy group; and P is a silane-linked reactive group; it includes a diol of formula Ila:

本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) A B c D 1238155 申請專利範圍與一種適當梦燒化試劑反應。 12. —種製備式Via化合物之方法：This paper size applies Chinese National Standard (CNS) A4 (210 X 297 mm) A B c D 1238155 Scope of patent application Reacts with a suitable dream firing reagent. 12. —Method for preparing compound of formula Via:

(Ι^ι)ηι 其中 η和nl獨立為1，2或3 ; 尺和Ri基可以相同或相異烷氧基；其 -二.一—.......... 包括在相轉移環境下以適當鹼在處理式V a_I對應化合物：(Ι ^ ι) ηι in which η and nl are independently 1, 2, or 3; Chi and Ri groups may be the same or different from each other; alkoxy groups; which-二. 一 -......... Included in the phase Treat the corresponding compound of formula V a_I with an appropriate base under a transfer environment:

Va (^ύηι 其中Ra為磺酸之殘基。 13. —種製備下式化合物之方法：Va (^ ύηι where Ra is a residue of a sulfonic acid. 13. —A method for preparing a compound of the formula:

(Ri)ni -10- O:\61\61888-921006.DOC5 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1238155 A8 B8 C8 D8 六、申請專利範圍其中 η和nl獨立為1，2或3 ; 尺和！^基可以相同或相異，各為氫或氧基；其包括將式IXa之對應化合物：(Ri) ni -10- O: \ 61 \ 61888-921006.DOC5 This paper size applies to Chinese National Standard (CNS) A4 specifications (210 X 297 mm) 1238155 A8 B8 C8 D8 Six, the scope of patent applications where η and nl Independent as 1, 2 or 3; ruler and! ^ Groups may be the same or different, each being hydrogen or oxy; it includes the corresponding compound of formula IXa:

IXa 添加於包括至少4當量適當還原劑之溶液。 14. 根據申請專利範圍第1 3項之方法，其中該還原劑為甲硼酸，二異丁基氫化銨，二異丙基氫化銨，或雙（2-甲氧乙氧基）氫化銨鈉。 15. —種式Ilia之化合物：IXa is added to a solution containing at least 4 equivalents of a suitable reducing agent. 14. The method according to item 13 of the scope of patent application, wherein the reducing agent is methylboronic acid, diisobutylammonium hydride, diisopropylammonium hydride, or sodium bis (2-methoxyethoxy) ammonium hydride. 15. — Compounds of formula Ilia:

其中 η和nl獨立為1，2或3 ; 尺和！^基可以相同或相異，各為氫或Ci-Q烷氧基；且 P為適當矽燒保護基。 -11- O:\61\61888-921006.DOC5 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐) 1238155 A8 B8 C8 D8 六、申請專利範圍 16.根據申請專利範圍第1 5項之化合物，其為式111之化合Where η and nl are independently 1, 2, or 3; The radicals may be the same or different, each being hydrogen or a Ci-Q alkoxy group; and P is a suitable silicon-fired protecting group. -11- O: \ 61 \ 61888-921006.DOC5 This paper size applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) 1238155 A8 B8 C8 D8 VI. Patent application scope 16. According to the patent application scope No. 1 5 Compound of the formula, which is a compound of formula 111

17. —種式IVa之化合物：17. — Compounds of formula IVa:

(^ι)ηι IVa 其中 η和nl獨立為1，2或3 ; 尺和！^基可-以相同或相異，各為氫或<^-06烷氧基； P為適當矽烷保護基；且 R a為磺酸之殘基。 18.根據申請專利範圍第1 7項之化合物，其為製備I V之化合物：(^ ι) ηι IVa where η and nl are independently 1, 2, or 3; ^ Groups may be the same or different, each being hydrogen or ^ -06 alkoxy; P is a suitable silane protecting group; and R a is a residue of a sulfonic acid. 18. The compound according to item 17 of the scope of patent application, which is a compound for preparing IV:

O:\61\61888-921006.DOC5 - 12 _ 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 8 8 8 8 A BCD 1238155 申請專利範圍 19. 一種式Va之化合物O: \ 61 \ 61888-921006.DOC5-12 _ This paper size applies to Chinese National Standard (CNS) A4 (210 X 297 mm) 8 8 8 8 A BCD 1238155 Application scope 19. A compound of formula Va

(^ι)ηΐ Va 其中 η和nl獨立為1，2或3 ; 尺和心基可以相同或相異，各為氫或Ci-Q烷氧基；且 R a為續酸之殘基。 20.根據申請專利範圍第1 9項之化合物，其為製備V之化合物：(^ ι) ηΐ Va where η and nl are independently 1, 2, or 3; the ruler and the heart group may be the same or different, and each is hydrogen or a Ci-Q alkoxy group; and R a is a residue of a continuous acid. 20. The compound according to item 19 of the scope of patent application, which is the compound for preparing V:

V -13 O:\61\61888-921006.DOC5 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐)V -13 O: \ 61 \ 61888-921006.DOC5 This paper size applies to China National Standard (CNS) A4 (210 X 297 mm)